MX2009000234A - Modulators of pharmacokinetic properties of therapeutics. - Google Patents

Modulators of pharmacokinetic properties of therapeutics.

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Publication number
MX2009000234A
MX2009000234A MX2009000234A MX2009000234A MX2009000234A MX 2009000234 A MX2009000234 A MX 2009000234A MX 2009000234 A MX2009000234 A MX 2009000234A MX 2009000234 A MX2009000234 A MX 2009000234A MX 2009000234 A MX2009000234 A MX 2009000234A
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MX
Mexico
Prior art keywords
alkyl
group
substituted
inhibitors
aryl
Prior art date
Application number
MX2009000234A
Other languages
Spanish (es)
Inventor
Manoj C Desai
Allen Yu Hong
Hongtao Liu
Lianhong Xu
Randall W Vivian
Original Assignee
Gilead Sciences Inc
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Publication date
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Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Publication of MX2009000234A publication Critical patent/MX2009000234A/en

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
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    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06008—Dipeptides with the first amino acid being neutral
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    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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Abstract

The present application provides for a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods and include the administration of such compounds with at least one additional therapeutic agent.

Description

MODU LATORS OF OWNERSHIP IS FARM ACO CIN ETHICS OF THERAPEUTIC PRODU CTS FIELD OF THE INVENTION This application relates, in general terms, to compounds and pharmaceutical compositions that modify, for example, improve, the pharmacokinetics of a co-administered drug, and to methods for modifying, for example, improving, the pharmacokinetics. of a drug by co-administering the compounds with the drug. ANTECED BEFORE THE INVENTION The oxidative metabolism by the cytochrome P450 enzymes is one of the primary mechanisms of drug metabolism. It may be difficult to maintain therapeutically effective blood plasma levels of drugs that are rapidly metabolized by cytochrome P450 enzymes. In accordance with the above, blood plasma levels of drugs that are susceptible to degradation by cytochrome P450 enzyme can be maintained or improved by co-administration of cytochrome P450 inhibitors, thereby improving pharmacokinetics. of the drug Although it is known that certain drugs inhibit cytochrome P450 enzymes, more and / or better inhibitors are desired for cytochrome P450 mono-oxygenase. In particular, it would be desirable to have inhibitors of cytochrome P450 mono-oxygenase, which do not have appreciable biological activity other than inhibition. of cytochrome P450. These inhibitors may be useful to minimize undesirable biological activity, for example side effects. In addition, it would be desirable to have P450 mono-oxygenase inhibitors that lack a significant level, or have a reduced level of protease inhibitory activity. These inhibitors could be useful to improve the effectiveness of anti-retroviral drugs, while minimizing the possibility of provoking viral resistance, especially against protease inhibitors. BR EVE DESCRIPTION OF THE INVENTION An aspect of the present application relates to compounds and pharmaceutical compositions that modify, for example, improve, the pharmacokinetics of a co-administered drug, for example, by inhibiting the mono-oxygenase of cytochrome P450. In one embodiment, the present application provides compounds having a structure according to formula I: Formula I or a pharmaceutically acceptable salt, solvate, and / or ester thereof, wherein, L1 is selected from the group consisting of -C (R6) 2-, -C (O) -, -S ( 0) 2-, -N (R7) -C (0) -, and -OC (O) -; L2 is a covalent bond, -C (R6) z- or -C (O) -; each L3 is independently a covalent bond, an alkylene, or substituted alkylene; each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, -O-, -CH2-0-, and -NH-; each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, ethercyclyl, and substituted heterocyclyl, with the proviso that when A is H, p is 0; Z1 and Z2 are each independently -O- or -N (R7) -; Y and X are independently selected from the group consisting of heterocyclyl and heterocyclyl-alkyl; each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R1, R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl-alkyl, and substituted aryl-alkyl; each R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxy-alkyl, hydroxy-alkyl, aryl-heteroalkyl, substituted aryl-heteroalkyl, aryl-alkyl, substituted aryl-alkyl, heterocyclyl-alkyl, heterocyclyl -substituted alkyl, amino-alkyl, amino-substituted alkyl, -alkylene-C (O) -OH, -alkylene-C (0) -Oalkyl, -alkylene-C (0) amino, -alkylene-C (O) - I rent; R4 and R6 are independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and -CN; m is 1 or 2; n is 0 or 1; and each p is independently 0 or 1. In another embodiment, the present application provides a pharmaceutical composition, which comprises a compound of the formula I, and a pharmaceutically acceptable excipient carrier. In another embodiment, the present application provides a pharmaceutical composition, which comprises a compound of the formula I, at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient. In another embodiment, the present application provides a method for improving the pharmacokinetics of a drug, which comprises administering to a patient treated with said drug, a therapeutically effective amount of a compound of the formula I, or a salt pharmaceutically acceptable, solvate, and / or ester thereof. In another embodiment, the present application provides a method for inhibiting cytochrome P450 mono-oxygenase in a patient, which comprises administering to a patient in need, an amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, effective to inhibit cytochrome P450 mono-oxygenase. In another embodiment, the present application provides a method for the treatment of a viral infection, e.g., HIV, which comprises administering to a patient in need, a therapeutically effective amount of a compound of the formula I, or a pharmaceutically salt acceptable, solvate, and / or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are metabolized by cytochrome P450 mono-oxygenase, and that are suitable for the treatment of a viral infection, by example, HIV. In another embodiment, the present application provides a pharmaceutical agent in combination, which comprises: a) a first pharmaceutical composition, which comprises a compound of the formula I, or a pharmaceutically acceptable salt, solvate, and / or ester thereof; and b) a second pharmaceutical composition, which comprises at least one additional active agent, which is metabolized by cytochrome P450 mono-oxygenase.
DETAILED DESCRIPTION Reference will now be made in detail to certain claims of the invention, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in conjunction with the claims listed, it will be understood that it is not intended to limit the invention to those claims. On the contrary, it is intended that the invention cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined by the claims. Definitions Unless otherwise reported, the following terms and phrases, as used herein, are intended to have the following meanings: When commercial names are used herein, applicants intend to independently include the product of the trade name and trade names. active ingredients of the product of the commercial name. As used herein, "a compound of the invention" or "a compound of the formula (I)" means a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, ester or stereoisomer thereof, or a physiologically functional derivative thereof. In a similar manner, with respect to the isolable intermediates, the phrase "a compound of the formula (number)" means a compound of that formula and the pharmaceutically acceptable salts, solvates and the physiologically functional derivatives thereof. "Alkyl" is a hydrocarbon that contains normal, secondary, tertiary, or cyclic carbon atoms. For example, an alkyl group may have from 1 to 20 carbon atoms (i.e., C1-C20 alkyl), from 1 to 10 carbon atoms (i.e., Ci-C10 alkyl), or from 1 to 6 carbon atoms (i.e., Ci-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH (CH3) 2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, - CH2CH (CH3) 2), 2-butyl (s-Bu, s-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH3) 3) , 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH2CH3) 2), 2-methyl-2-butyl (-C (CH3) 2CH2CH3), 3-methyl-2-butyl (-CH (CH3) CH (CH3) 2), 3-methyl-1-butyl (-CH2CH2CH (CH3) 2), 2-methyl-1-butyl (-CH2CH ( CH3) CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3) CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3) (CH2CH2CH3)), 2-methyl-2-pentyl (-C ( CH3) 2CH2CH2CH3), 3-methyl-2-pentyl (-CH (CH3) CH (CH3) CH2CH3), 4-methyl-2-pentyl (-CH (CH3) CH2CH (CH3) 2), 3-methyl-3 -pentyl (-C (CH3) (CH2CH3) 2), 2-methyl-3-pentyl (-CH (CH2CH3) CH (CH3) 2), 2,3-dimethyl-2-butyl (-C (CH3) 2CH (CH3) 2), 3,3-dimethyl-2-butyl (-CH ( CH3) C (CH3) 3, and octyl (- (CH2) 7CH3).
"Alkoxy" means a group having the formula -O-alkyl, wherein an alkyl group, as defined above, is attached to the progenitor molecule by means of an oxygen atom. Serving of alkyl of an alkoxy group may have from 1 to 20 carbon atoms (i.e., C 1 -C 6 alkoxy), from 1 to 12 carbon atoms (i.e., alkoxy) or from 1 to 6 carbon atoms (i.e., Ci-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-0-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), terbutoxyl (-0-C (CH3) 3 or -OtBu), and similar. "Haloalkyl" is an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced with a halogen atom. The alkyl portion of the haloalkyl group may have from 1 to 20 carbon atoms (i.e., haloCi-C20 alkyl), from 1 to 10 carbon atoms (i.e., haloalkyl d-C12), or from 1 to 6 carbon atoms (i.e., haloCi-C6 alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like. "Alkenyl" is a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms, with at least one unsaturation site, ie, a carbon-carbon double bond, sp2. For example, an alkenyl group can have from 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), from 2 to 12 carbon atoms (i.e., C2-Ci2 alkenyl), or from 2 to 6 carbon atoms (ie, C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH = CH2), allyl (-CH2CH = CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2 CH = CH2) .
"Alkynyl" is a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one unsaturation site, ie, a carbon-carbon triple bond, sp. For example, an alkynyl group can have from 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), from 2 to 12 carbon atoms (i.e., C2-C12 alkynyl), or from 2 to 6 carbon atoms (ie, C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C = CH), propargyl (-CH2C = CH), and the like. "Alkylene" refers to a saturated, branched or straight chain, or cyclic hydrocarbon radical, having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH (CH3) -), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH (CH2CH3) -), 1,2-propyl (-CH2CH (CH3) -), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.
"Alkenylene" refers to a branched or straight chain, or cyclic unsaturated hydrocarbon radical, having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of an alkene progenitor. For example, an alkenylene group it can have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH = CH-). "Alkynylene" refers to a branched or straight chain, or cyclic unsaturated hydrocarbon radical, having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of an alkyne progenitor. For example, an alkynylene group may have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C = C-), propargyl (-CH2C = C-), and 4-pentynyl (-CH2CH2CH2C = CH-). "Amino" means a group -NH2 or -N 2, wherein the "R" groups are independently H, alkyl, carbocyclyl (substituted or unsubstituted, including saturated or partially unsaturated cycloalkyl and aryl groups), heterocyclyl (substituted or unsubstituted, including saturated or unsaturated hetero-cycloalkyl and heteroaryl groups), aryl-alkyl groups (substituted or unsubstituted) or aryl-alkyl (substituted or unsubstituted). Non-limiting examples of amino groups include -NH2, -NH (alkyl), -NH (carbocyclyl), -NH (heterocyclyl), -N (alkyl) 2, -N (carbocyclyl) 2, -N (heterocyclic) Lo) 2, -N (alkyl) - (carbocyclyl), -N (alkyl) - (heterocyclyl), -N (carbocyclyl) - (heterocyclyl), etc., wherein alkyl, carbocyclyl, and heterocyclyl may be substituted or unsubstituted and as defined and described herein. Amino "substituted" or "protected" means an amino-alkyl as described and defined herein, wherein an H of the amino group is replaced, for example, with acyl groups, for example conventional amine protecting groups, such as 9-fluorenyl-methyl carbamate ( "Fmoc"), tert-butyl carbamate ("Boc"), benzyl carbamate ("Cbz"), acetyl, trifluoro-acetyl, phthalimidyl, triphenyl-methyl, p-toluene-sulfonyl ("Tosyl"), methyl-sulfonyl ( "mesilo"), etc. "Amino-alkyl" means an acyclic alkyl radical, wherein one of the hydrogen atoms bonded to a terminal carbon atom, typically a terminal or sp3 carbon atom, is replaced with an amino radical, as defined and describes in the present. Non-limiting examples of amino-alkyl include -CH2-NH2, -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH2CH2CH2CH2-NH2, -CH2CH (CH3) -NH2, -CH2CH2CH (CH3) -NH2, -CH2-NH (CH3), -CH2CH2-NH (CH3), -CH2CH2CH2-NH (CH3), -CH2CH2CH2CH2-NH (CH3), -CH2CH (CH3) -NH (CH3), -CH2CH2CH (CH3) -NH (CH3), -CH2-N (CH3) 2, -CH2CH2-N (CH3) 2l -CH2CH2CH2-N (CH3) 2, -CH2CH2CH2CH2-N (CH3) 2, -CH2CH (CH3) -N (CH3) 2, -CH2CH2CH ( CH3) -N (CH3) 2, -CH2-NH (CH2CH3), -CH2CH2-NH (CH2CH3), -CH2CH2CH2-NH (CH2CH3), -CH2CH2CH2CH2-NH (CH2CH3), -CH2CH (CH3) -NH (CH2CH3 ), -CH2CH2CH (CH3) -NH (CH2CH3), -CH2-N (CH2CH3) 2, -CH2CH2-N (CH2CH3) 2, -CH2CH2CH2-N (CH2CH3) 2, -CH2CH2CH2CH2-N (CH2CH3) 2 , -CH2CH (CH3) -N (CH2CH3) 2, -CH2CH2CH (CH3) -N (CH2CH3) 2, etc. "Substituted" or "protected" amino-alkyl means an amino-alkyl as described and defined herein, wherein the H or amino group is replaced, by example, with acyl groups, for example conventional amine protecting groups, such as 9-fluorenyl-methyl carbamate ("Fmoc"), terbutyl carbamate ("Boc"), benzyl carbamate ("Cbz"), acetyl, trifluoro-acetyl, phthalimidyl, triphenyl-methyl, p-toluene-sulfonyl ("Tosyl"), methyl-sulfonyl ("mesyl"), etc. "Aryl" means an aromatic hydrocarbon radical derived by the removal of a hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to, the radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Aryl-alkyl" refers to an acyclic alkyl radical, wherein one of the hydrogen atoms bonded with a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical aryl alkyl groups include, but are not limited to, benzyl, 2-phenyl-ethan-1-yl, naphthyl-methyl, 2-naphthyl-ethan-1-yl, naphthobenzyl, 2-naphthiophenyl-ethan-1 - ilo, and similar. The aryl alkyl group may comprise from 6 to 20 carbon atoms, for example, the alkyl moiety is from 1 to 6 carbon atoms, and the aryl moiety is from 6 to 14 carbon atoms. "Aryl-alkenyl" refers to an acyclic alkenyl radical, wherein one of the hydrogen atoms bonded with a carbon atom, typically a terminal or sp3 carbon atom, but also a sp2 carbon atom, is replaced with an aryl radical. The aryl portion of the aryl alkenyl may include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the aryl alkenyl may include, for example, any of the alkenyl groups disclosed in the present. The aryl-alkenyl group may comprise from 6 to 20 carbon atoms, for example, the alkenyl fraction is from 1 to 6 carbon atoms, and the aryl fraction is from 6 to 14 carbon atoms. "Aryl-alkynyl" refers to an acyclic alkynyl radical wherein one of the hydrogen atoms bonded with a carbon atom, typically a terminal or sp3 carbon atom, but also an sp carbon atom, is replaced with a radical of aril. The aryl portion of the aryl alkynyl may include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl may include, for example, any of the alkynyl groups disclosed in the present. The aryl alkynyl group may comprise from 6 to 20 carbon atoms, for example, the alkynyl fraction is from 1 to 6 carbon atoms, and the aryl fraction is from 6 to 14 carbon atoms. The term "substituted" with reference to alkyl, alkylene, aryl, aryl-alkyl, heterocyclyl, heteroaryl, carbocyclyl, etc., eg, "substituted alkyl", "substituted alkylene", "substituted aryl", "substituted aryl-alkyl" "," substituted heterocyclyl ", and" substituted carbocyclyl "mean alkyl, alkylene, aryl, aryl-alkyl, heterocyclyl, carbocyclyl, respectively, wherein one or more Hydrogen are each independently replaced with a substituent that is not hydrogen. Typical substituents include, but are not limited to, -X, -R, -O, = 0, -OR, -SR, -S-, -NR2, -N + R3, = NR, -CX3, -CN, -OCN, -SCN, -N = C = 0, -NCS, -NO, -N02, = N2, -N3, -NHC (= 0) R, -NHS (= 0) 2R, -C (= 0) R, -C (= 0) NRR, -S (= 0) 20", -S (= 0) 2OH, -S (= 0) 2R, -S (= 0) 2OR, -S (= 0) 2NR , -S (= 0) R, -0P (= 0) (OR) 2, -P (= 0) (OR) 2, -P (= 0) - (0) 2, -PC = 0) - ( OH) 2, -P (0) - (OR) - (0"), -C (= 0) R, -C (= 0) OR, -C (= 0) X, -C (S) R, -C (0) OR, -C (0) 0C (S) OR, -C (0) SR, -C (S) SR, -C (0) NRR, -C (S) NRR, - C (= NR) NRR, wherein each X is independently a halogen: F, Cl, Br, or I; and each R is independently H, alkyl, aryl, aryl-alkyl, a heterocycle, or a protecting group or a prodrug moiety. The alkylene, alkenylene, and alkynylene groups may also be similarly substituted. When the number of carbon atoms is designated for a substituted group, the number of carbon atoms refers to the group, and not to the substituent (unless otherwise indicated). For example, a d.4-substituted alkyl refers to an alkyl of 1 to 4 carbon atoms which may be substituted with groups having, for example, more than 4 carbon atoms. The term "pro-drug", as used herein, refers to any compound that, when administered to a biological system, generates the drug substance, ie, the active ingredient, as a result of spontaneous chemical reactions, chemical reactions catalyzed by enzymes, photolysis, and / or metabolic chemical reactions. Therefore, a The drug is a covalently modified analogue or a latent form of a therapeutically active compound. One skilled in the art will recognize that the substituents and other fractions of the compounds of the formula I, should be selected such that they provide a compound that is sufficiently stable to provide a pharmaceutically useful compound, which can be formulated into a pharmaceutical composition. acceptably stable. It is contemplated that compounds of formula I having such stability fall within the scope of the present invention. "Heteroaryl" refers to an alkyl group, wherein one or more carbon atoms have been replaced with a heteroatom, such as O, N, or S. For example, if the carbon atom of the alkyl group that is bonded to the progenitor molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, a alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N (CH3) 2, etc.), or a thioalkyl group (e.g., -SCH3). If a non-terminal carbon atom of the alkyl group that is not bound to the progenitor molecule is replaced with a heteroatom (eg, O, N, or S), the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g. -CH2CH2-0-CH3, etc.), an alkyl-amine (e.g., -CH2NHCH3, -CH2N (CH3) 2, etc.), or a thioalkyl ether (e.g., -CH2-S-CH3). If a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (for example, -CH2CH2-OH), an amino-alkyl group (for example, -CH2NH2), or a thiol-alkyl group (for example, -CH2CH2-SH) ). A heteroalkyl group can have, for example, from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. A heteroalkyl group Ci-C6 means a heteroalkyl group having from 1 to 6 carbon atoms. "Heterocycle" or "heterocyclyl", as used herein, includes, by way of example and not limitation, the heterocycles described in Paquette, Leo A .; Principles of Modera Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley &Sons, New York, 1950 to the present), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82: 5566. In a specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined herein, wherein one or more (e.g. , 3, or 4) carbon atoms have been replaced with a heteroatom (eg, O, N, or S). The terms "heterocycle" or "heterocyclyl" include the saturated rings, the partially unsaturated rings, and the aromatic rings (ie, the heteroaromatic rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein, including carbonyl groups. A non-limiting example of a heterocyclyl substituted by carbonyl is: Examples of the heterocycles include, by way of example and not limitation, pyridyl, dihydro-pyridyl, tetrahydro-pyridyl (piperidyl), thiazolyl, tetrahydro-thiophenyl, tetrahydro-thiophenyl oxidized with sulfur, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, tianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolinyl, tetrahydro-furanyl, tetrahydro-quinolinyl, tetrahydro-isoquinolinyl, decahydro-quinolinyl, octahydro-isoquinolinyl, azocinyl, triazinyl, 6H-1, 2,5-thiadiazinyl, 2H, 6H-1, 5,2-dithiazinyl, thienyl, thiantrenyl, pyranyl, isobenzo-furanyl, chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, Sothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1 H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-car bazolilo, carbazolyl, ß-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pirazolidinito, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl: By way of example and not limitation, the carbon-linked heterocycles are linked at the 2, 3, 4, 5, or 6 position of a pyridine, at the 3, 4, 5, or 6 position of a pyridazine, at position 2, 4, 5, or 6 of a pyrimidine, in position 2, 3, 5, or 6 of a pyrazine, in position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydro-pyrrole; in position 2, 4, or 5 of an oxazole, imidazole or thiazole, in position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, in the 2 or 3 position of an aziridine, in position 2, 3, or 4 of an azetidine, in position 2, 3, 4, 5, 6, 7, or 8 of a quinoline, or in position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline . Still more typically, carbon-linked heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl., 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example and not limitation, the nitrogen-linked heterocycles are linked at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1 H-indazole; in position 2 of an isoindol or isoindoline; in position 4 of a morpholine, and in position 9 of a carbazole or ß-carboline. Still more typically, heterocycles linked with nitrogen include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, -pyrazolyl, and 1-piperidinyl. "Heterocyclyl-alkyl" refers to an acyclic alkyl radical wherein one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl radical (ie, a fraction of heterocyclyl-alkylene). Typical heterocyclyl-alkyl groups include, but are not limited to, heterocyclyl-CH2-, heterocyclyl-CH (CH3) -, heterocyclyl-CH2CH2-, 2- (heterocyclyl) -ethan-1-yl, and the like, wherein the "Heterocyclyl" portion includes any of the heterocyclyl groups described above, including those described in Principies of Modern Heterocyclic Chemistry. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl-alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable The heterocyclyl-alkyl group comprises from 2 to 20 carbon atoms, for example, the alkyl portion of the heterocyclyl-alkyl group is from 1 to 6 carbon atoms, and the heterocyclyl fraction is from 1 to 14 carbon atoms. Examples of heterocyclyl alkyls include, by way of example and not limitation, 5-membered heterocycles containing sulfur, oxygen, and / or nitrogen, such as thiazolyl-methyl, 2-thiazolyl-ethan-1-yl, imidazolyl-methyl, oxazolyl-methyl, thiadiazolyl-methyl, etc., and 6-membered heterocycles containing sulfur, oxygen, and / or nitrogen, such as piperidinyl-methyl, piperazinyl-methyl, morpholinyl- methyl, pyridinyl-methyl, pyridyzyl-methyl, pyrimidyl-methyl, pi-razi-nyl-methyl, etc. "Heterocyclyl-alkenyl" refers to an acyclic alkenyl radical wherein one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp2 carbon atom, is replaced. with a heterocyclyl radical (that is, a heterocyclyl-alkenylene fraction). The heterocyclyl portion of the heterocyclyl-alkenyl group includes any of the heterocyclic groups described herein, including that described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl-alkenyl group includes any of the alkenyl groups made known in the present. A person skilled in the art will also understand that the hete rocyclyl group can be attached to the alkenyl portion of the heterocyclyl-alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the group resulting chemically stable. The heterocyclyl-alkenyl group comprises from 3 to 20 carbon atoms, for example, the alkenyl portion of the heterocyclyl-alkenyl group is from 2 to 6 carbon atoms, and the heterocyclyl group is from 1 to 14 carbon atoms. carbon. "Heterocyclyl-alkynyl" refers to an acyclic alkynyl radical wherein one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp carbon atom, is replaced with a carbon atom. heterocyclyl radical (ie, a heterocyclyl-alkynylene fraction). The heterocyclyl portion of the heterocyclyl-alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principies of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl-alkynyl group includes any of the alkynyl groups disclosed in the present. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl-alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable The heterocyclyl-alkynyl group comprises from 3 to 20 carbon atoms, for example, the alkynyl portion of the heterocyclyl-alkynyl group is from 2 to 6 carbon atoms, and the heterocyclyl fraction is from 1 to 14 carbon atoms. "Heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of the heteroaryl rings include all those listed in the definition of "heterocyclyl," including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzo-furanyl, benzo-thiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazil, pyrimidyl, pyrazyl, etc.
"Carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.), or aromatic, ring having from 3 to 7 carbon atoms as a monocycle, from 7 to 12 carbon atoms as a bicyclo, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have from 3 to 6 ring atoms, and still more typically 5 or 6 ring atoms. The bicyclic carbocycles have from 7 to 12 ring atoms, for example configured as a bicyclo [4.5], [5.5], [5,6] or [6.6] system, or 9 or 10 ring atoms configured as a bicyclo system [5,6] or [6,6], or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl the, cyclobutyl, cyclopentyl, 1-cyclopent-1 -enilo, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1 -enilo 1 -cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclic carbocycles include naphthyl. "Aryl-heteroalkyl" refers to a heteroalkyl as defined herein, wherein a hydrogen atom (which may be attached to either a carbon atom or a heteroatom), has been replaced with an aryl group as is defined in the present. The aryl groups may be linked to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting aryl heteroalkyl group provides a chemically stable moiety. For example, an aryl-heteroalkyl group may have the general formulas: -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. In addition, any of the alkylene moieties of the above general formulas may be further substituted with any of the substituents defined or exemplified herein. "Heteroaryl-alkyl" refers to an alkyl group, as defined herein, wherein a hydrogen atom has been replaced with a heteroaryl group as defined herein. Nonlimiting examples of heteroaryl-alkyl include -CH2-pyridinyl, -CH2-pyrrolyl, -CH2-indolyl, -CH2-isoindolyl, -CH2-purinyl, -CH2-furanyl, -CH2-thienyl, -CH2-benzofuranyl, - CH2-benzothiophenyl, -CH2-carbazolyl, -CH2-imidazolyl, -CH2-thiazolyl, -CH2-isoxazolyl, -CH2-pyrazolyl, -CH2-isothiazolyl, -CH2-quinolllo, -CH2-isoqulnolilo, -CH2-pyridazyl, - CH2-pyrimidyl, -CH2-pyrazyl, -CH (CH3) -pyridinyl, -CH (CH3) -pyrrolyl, -CH (CH3) -oxazolyl, -CH (CH3) -indolyl, -CH (CH3) -isoindolyl, - CH (CH3) -purinyl, -CH (CH3) -furanyl, -CH (CH3) -thienyl, -CH (CH3) -benzofuranilo, -CH (CH3) -benzotiofenilo, -CH (CH3) -carbazolyl, -CH ( CH3) -imidazolyl, -CH (CH3) -thiazolyl, -CH (CH3) -isoxazolilo, -CH (CH3) -pirazolilo, -CH (CH3) -isotiazolilo, -CH (CH3) -quinolyl, -CH (CH3) isoquinolyl, -CH (CH 3) -pyridazil, -CH (CH 3) -pyrimidyl, -CH (CH 3) -pyrazyl, etc. The term "optionally substituted", with reference to a particular fraction of the compound of the formula I (for example, an optionally substituted aryl group), refers to a fraction that has O, 1, 2, or more substituents. "Ac" means acetyl (-C (0) CH3). "Ac20" means acetic anhydride. "DCM" means dichloromethane (CH2Cl2). "DIBAL" means di-isobutyl-aluminum hydride. "DMAP" means dimethyl-amino-pyridine. "EDC" means 1- (3-dimethyl-amino-propyl) -3-ethyl-carbodi-imide. "Et" means ethyl. "EtOAc" means ethyl acetate. "HOBt" means N-hydroxy-benzotriazole. "Me" means methyl (-CH3). "MeOH" means methanol. "MeCN" means propyl. "i-Pr" means isopropyl (-CH (CH 3) 2). "i-PrOH" means isopropanol. "rt" means room temperature. "TFA" means trifluoroacetic acid. "THF" means tetrahydrofuran. The term "chiral" refers to molecules that have the property of not overcoming the mirror image component, while the term "achiral" refers to molecules that can be superimposed on their mirror image component. The term "stereoisomers" refers to compounds that have an identical chemical constitution, but that differ with respect to the configuration of atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality, and whose molecules are not mirror images of one another. The diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated according to high resolution analytical methods, such as electrophoresis and chromatography. "Enantiomers" refers to two stereoisomers of a compound that are mirror images that can not be superimposed on one another. The stereochemical definitions and conventions used herein generally follow S. P. Parker, Editor, cGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistrv of Orqanic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of polarized light into planes. In the description of an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule around its chiral centers. The prefixes d and I or (+) and (-) are used to designate the sign of rotation of plane polarized light by the compound, meaning (- = or 1 that the compound is levorotatory.) A compound with prefix (+) or d is dextrorotatory For a given chemical structure, these stereoisomers are identical, except that they are mirror images or not of the other. A specific stereoisomer may also be referred to as a nantiomer, and a mixture of these isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur when there has not been stereoselection or stereospecificity in a chemical reaction or in a process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Protective Groups In the context of the present invention, the protecting groups include the pro-drug fractions and the chemical protecting groups. Protective gums are available, are commonly known and used, and are optionally used to prevent the senescent reactions with the protected group during synthetic procedures, ie, routes or methods for preparing the compounds of the invention. . For the most part, the decision on which groups to protect, when it is to be cleared, and the nature of the chemical protective group "PG", will depend on the chemistry of the reaction against which it will be protected (eg conditions acidic, basic, oxidative, reductive, or other conditions), and of the intended direction of the synthesis. PG groups do not need to be, and in general are not, equal, if the compound it is substituted with multiple PGs. In general, PG will be used to protect functional groups, such as carboxyl, hydroxyl, thio, or amino groups, and therefore, prevent side reactions or otherwise facilitate synthetic efficiency. The order of deprotection to provide free unprotected groups depends on the intended direction of the synthesis and on the reaction conditions to be encountered, and can be presented in any order, as determined by the expert. Different functional groups of the compounds of the invention can be protected. For example, protecting groups for the -OH groups (whether the hydroxyl, carboxylic acid, phosphonic acid, or other functions) include the "ether or ester forming groups". The ether or ester forming groups are capable of functioning as chemical protecting groups in the synthetic schemes stipulated herein. However, some hydroxyl or thio protecting groups are not ether or ester forming groups, as will be understood by those skilled in the art, and are included with the amides, discussed below. A very large number of hydroxyl protecting groups and amide-forming groups, and the corresponding chemical dissociation reactions, are described in Protective Groups in Orqanic Svnthesis. Theodora W. Greene and Peter G. M. Wuts (John Wiley &; Sons, Inc., New York, 1999, ISBN 0-471-16019-9) ("Greene"). See also Kocienski, Philip J .; Protectinq Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated herein by reference in its entirety. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups , pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protective groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid, and other acid protecting groups, see Greene as provided below. These groups include, by way of example and not limitation, esters, amides, hydrazides, and the like. Ether and ester forming protecting groups The ester forming groups include: (1) the phosphonate ester-forming groups, such as the phosphonamidate esters, the phosphorothioate esters, the phosphonate esters, and the phosphono-bis-amidates; (2) the carboxyl ester forming groups, and (3) the sulfur ester forming groups, such as sulfonate, sulfate, and sulfinate. Metabolites of the compounds of the invention Also within the scope of this invention are the in vivo metabolic products of the compounds described herein. These products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the compound administered, primarily due to the enzymatic processes. In accordance with the foregoing, the invention includes the compounds produced by a process comprising contacting a compound of this invention with a mammal, for a period of time sufficient to produce a metabolic product thereof. These products are typically identified by the preparation of a radiolabeled compound of the invention (eg, C14 or H3), their parenteral administration, in a detectable dose (eg, greater than about 0.5 milligrams / kilogram) to an animal, such as rat, mouse, guinea pig, monkey, or man; Allow enough time for metabolism to occur (typically from about 30 seconds to 30 hours), and isolate your conversion products from urine, blood, or other biological samples. These products are easily isolated, because they are marked (others are isolated by the use of antibodies capable of binding to the epitopes that survive in the metabolite). The structures of the metabolites are determined in a conventional manner, for example by MS or NMR analysis. In general, metabolite analysis is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The products of the conversion, provided they are not otherwise found in vivo, are useful in diagnostic assays for the therapeutic dosing of the compounds of the invention, even when they do not possess an anti-infective activity by themselves.
Compounds of formula I In one embodiment, the present application provides the compounds according to formula I, as described herein. In another embodiment of the compounds of the formula I, n is 1. In another embodiment of the compounds of the formula I, n is 0. In another embodiment of the compounds of the formula I, n is 1 and L2 is -CH ( R6) -, wherein R6 is selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl. In another embodiment of the compounds of the formula I, n is 1 and L2 is -CH2-. In another embodiment of the compounds of formula I, n is 1 and L2 is -C (O) -. In another embodiment of the compounds of the formula I, n is 1 and Y is heterocyclyl-alkyl. In another embodiment of the compounds of the formula I, n is 1 and Y-RB is -CH2- (substituted heteroaryl). In another embodiment of the compounds of formula I, n is 1 and Y-R8 is: In another embodiment of the compounds of formula I, n is 1 and Y-R8 is: wherein R is alkyl, for example 2-propyl. In another embodiment of the compounds of the formula I, n is 1 X is heterocyclyl-alkyl. In another embodiment of the compounds of the formula I, n is 1 X is -CH 2 -heteroaryl. In another embodiment of the compounds of the formula I, n is 1 X-R is: In another embodiment of the compounds of formula 1, n is 1 X-R 9 is: In another embodiment of the compounds of formula I, n is 1 Z1 is -N (R7) -. In another embodiment of the compounds of the formula I, n is 1 Z1 is -N (alkyl) - or -N (carbocyclyl) -. In another embodiment of the compounds of formula I, n is 1 Z1 is -N (CH3) - or -N (cyclopropyl) -. In another embodiment of the compounds of the formula I, n is 1 Z1 is -NH-. In another embodiment of the compounds of formula I, n is 1 each A is independently aryl or substituted aryl. In another embodiment of the compounds of the formula I, n is 1 each A is phenyl. In another embodiment of the compounds of the formula I, n is 1 · and each A is phenyl and each p is 0. In another embodiment of the compounds of the formula I, n is 1 and R2 is H, alkyl, substituted alkyl, or heteroalkyl. In another embodiment of the compounds of the formula I, n is 1 and R2 is 2- propyl, methyl, -CH2-0-benzyl, -CH (CH3) - (0-t-Bu), or -CH (CH3) - (OH) In another embodiment of the compounds of formula I, L 1 is -C (O) -; each A is independently aryl, substituted aryl, alkyl, or substituted alkyl; R1 is H or alkyl; each R2 is independently H, alkyl, substituted alkyl, or heteroalkyl; R3, R4, R5, and R6 are each H; each R7 is independently H, alkyl, or carbocyclyl; R8 is H or alkyl; R9 is H; X and Y are both heterocyclyl-alkyl; Z2 is -O-; and p is 0. In another embodiment of the compounds of the formula I, each A is phenyl; R is H or -CH3; each R2 is H, methyl, ethyl, 2-propyl, -CH2-0-benzyl, -CH (CH3) -OH, or -CH (CH3) - (0-t-Bu); each R7 is H, methyl or cyclopropyl; R8 is H or 2-propyl; X is: In another embodiment, the compounds of formula I have following general formula IA: Formula IA. In another embodiment of the compounds of the formula IA, Z1 is -N (R7) -. In a particular embodiment, R7 is H. In another particular embodiment, R7 is alkyl, for example any of the alkyl groups disclosed herein. In another particular embodiment, R7 is heteroalkyl, for example any of the heteroalkyl groups made known in the present. In another particular embodiment, R7 is substituted or unsubstituted carbocyclyl, wherein, for example, the carbocyclyl is any of the carbocyclyl groups disclosed herein. In another particular embodiment, R7 is substituted or unsubstituted heterocyclyl, wherein, for example, the heterocyclyl is any of the heterocyclyl groups disclosed herein. In another embodiment of the compounds of formula IA, Z1 is -O-. In another embodiment of the compounds of the formula IA, L2 is -C (R6) 2-, wherein each R6 is H. In another embodiment of the compounds of the formula IA, L2 is -C (R6) 2-, in wherein each R6 is independently H or alkyl, and the alkyl includes any alkyl disclosed herein. In another embodiment of the compounds of formula IA, L2 is -C (R6) 2-, wherein one R6 is H and the other R6 is alkyl, wherein this alkyl includes any alkyl disclosed herein. In another embodiment of the compounds of the formula IA, m is 1 and R2 is H. In another embodiment of the compounds of the formula IA, m is 1 and R2 is alkyl, wherein this alkyl includes any alkyl disclosed in I presented. In another embodiment of the compounds of formula IA, m is 1 and R2 is isopropyl. In another embodiment of the compounds of formula IA, m is 1 and R2 is sobutyl. In another embodiment of the compounds of formula IA, m is 1 and R2 is ethyl. In another embodiment of the compounds of the formula IA, m is 1 and R2 is methyl. In another embodiment of the compounds of the formula IA, m is 2 and each R2 is independently selected from H and alkyl. In another embodiment of the compounds of formula IA, m is 2 and each R2 is H. In another embodiment, the compounds of the formula I have the following general formula I B: Formula IB In another embodiment of the compounds of the formula I B, Z1 is -N (R7) -. In a particular embodiment, R7 is H. In another particular embodiment, R7 is alkyl, for example any of the alkyl groups disclosed herein. In another particular embodiment, R7 is heteroalkyl, for example any of the heteroalkyl groups disclosed herein. In another particular embodiment, R7 is substituted or unsubstituted carbocyclyl, where, for example, this carbocyclyl is any of the carbocyclyl groups disclosed at the moment. In another particular embodiment, R7 is substituted or unsubstituted heterocyclyl, wherein, for example, this heterocyclyl is any of the heterocyclyl groups disclosed herein. In another embodiment of the compounds of the formula IB, Z1 is -OR-. In another embodiment of the compounds of the formula IB, L2 is -C (R6) 2-, wherein each R6 is H. In another embodiment of the compounds of the formula IB, L2 is -C (R6) 2-, in wherein each R6 is independently H or alkyl, and the alkyl includes any alkyl disclosed herein. In another embodiment of the compounds of formula IB, L2 is -C (R5) 2-, wherein one R6 is H and the other R6 is alkyl, wherein this alkyl includes any alkyl disclosed herein. In another embodiment of the compounds of the formula IB, R8 and R9 are both H. In another embodiment of the compounds of the formula IB, R8 and R9 are independently selected from H and alkyl, wherein this alkyl includes any given alkyl to know in the present.
In another embodiment, the compounds of the formula I have one of the following structures: ?? 40 ?? 42 ?? 25 ?? ?? including stereoisomers or mixtures of stereoisomers thereof. One skilled in the art will recognize that stereoisomers or mixtures of stereoisomers of the compounds of the present application include enantiomers, diastereomers, and other stereoisomers. For example, to: The stereoisomers contemplated include at least: as well as mixtures of two or more of these stereoisomers. In still another embodiment of the compounds of formula I, L 1 is -C (R 6) 2-, -C (O) -, -S (02) -, -N (R 7) -C (0) -, - OC (O) -. When L1 is -C (R6) 2-, each R6 is independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substituted alkyl, and heteroalkyl are as defined and exemplified in the present. Non-limiting examples of -C (R6) 2- include -CH2-, -CH (alkyl) -, -CH (substituted alkyl) -, -CH (heteroalkyl) -, -C (alkyl) 2-, -C ( substituted alkyl) 2-, -C (heteroalkyl) 2-, -C (alkyl) - (substituted alkyl) -, -C (heteroalkyl) - (substituted alkyl) -, and -C (alkyl) - (heteroalkyl) -, wherein alkyl, substituted alkyl, and heteroalkyl are as defined and exemplified herein. When L1 is -N (R7) -C (0) -, R7 is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl , heterocyclyl, or substituted heterocyclyl are as defined and exemplified herein. In yet another embodiment of the compounds of formula I, L2 is -C (R6) 2- or -C (O) -. When L2 is -C (R6) 2-, each R6 is selected independently from H, alkyl, substituted alkyl or heteroalkyl, wherein each alkyl, substituted alkyl, or heteroalkyl may include any of the alkyl, substituted alkyl, or heteroalkyl groups defined or disclosed herein. Non-limiting examples of -C (R6) 2- include -CH2-, -CH (CH3) -, -CH (-CH2CH3) -, -CH (-CH2CH2CH3) -, -CH (-CH (CH3) 2) -, -CH (-CH2CH2CH2CH3) -, -CH (-CH2CH (CH3) 2) -, - CH (-CH (CH3) CH2CH3) -, -CH (-C (CH3) 3) -, -C (CH3) 2-, -CH (OCH3) -, -CH (CH2OH) -, -CH (CH2CH2 OH) -, etc. In still another embodiment of the compounds of the formula I, each L3 is independently a covalent bond, an alkylene or substituted alkylene. When any L3 is an alkylene, non-limiting examples of alkylene include any of the defined or disclosed alkyl ethers. When any L3 is a substituted alkylene, non-limiting examples of substituted alkylene include any of the substituted alkylene substituted or disclosed herein. For example, substituted alkyls include alkyl substituted with one or more -OH groups, alkyl substituted with one or more ether groups, for example, a -O-Bn group, alkyl substituted with one or more halogens, or alkylene substituted with combinations of two or more substituents (e.g., -OH and halogen, halogen and ether, etc.). In still another embodiment of the compounds of formula I, each L3 is the same, ie, each L3 is the same alkylene group or substituted alkylene. In still another embodiment of the compounds of the formula I, each L3 is different, that is, one L3 is an alkylene and the other L3 is a substituted alkylene, one L3 is an alkylene and the other L3 is a different alkylene, or a L3 is a substituted alkylene, and the other L3 is a different substituted alkylene. In yet another embodiment of the compounds of the formula I, each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, -O-, -CH2-0-, and -NH-. When L 4 is alkylene, this alkylene includes any alkylene defined or exemplified herein. When L 4 is substituted alkylene, the substituent includes any alkylene defined or exemplified herein, substituted by one or more substituents as defined herein. In still another embodiment of the compounds of the formula I, both L4 groups are the same, ie both L4 groups are a covalent bond, both are -O-, both are -CH2-0- (where the CH2 group is attached either to fraction "A" or to fraction "Ar" of formula I), both are substituted or unsubstituted alkylene, or both are -NH-. In yet another embodiment of the compounds of formula I, each L4 is different. For example, one L4 is a covalent bond and the other L4 is -O-, one L4 is a covalent bond and the other L4 is -CH2-0- (where the CH2 group is attached to either the "A" fraction or to the "Ar" fraction of formula I), an L4 is a covalent bond and the another L4 is -NH-, one L4 is an -O- and the other L4 is -CH2-0- (where the CH2 group is linked either to the "A" fraction or to the "Ar" fraction of the formula I), one L4 is -O- and the other L4 is -NH-, one L4 is -CH2-O- (where the CH2 group is linked either to the "A" fraction or to the "Ar" fraction "of the formula I) and the other L4 is -NH-, one L4 is a covalent bond and the other L4 is a substituted or unsubstituted alkylene, one L4 is a substituted alkylene and the other L4 is an unsubstituted alkylene, an L4 is one substituted or unsubstituted alkene and the other L4 is -O-, one L4 is a substituted or unsubstituted alkylene and the other L4 is -CH2-0- (wherein the CH2 group is attached to either the "A" fraction or to the "Ar" fraction of the formula I), or one L 4 is substituted or unsubstituted alkylene and the other L 4 is -NH-. In still another embodiment of the compounds of the formula I, each A is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl, with the proviso that, when A is H, p is 0. When any A is alkyl, this alkyl includes any alkyl defined or exemplified herein. When any A is substituted alkyl, this alkyl includes any alkyl defined or exemplified herein, substituted with one or more of any substituents defined or exemplified herein. When any A is aryl, this aryl includes any aryl defined or exemplified herein. When any A is substituted aryl, this aryl includes any aryl defined or exemplified herein, substituted with one or more of any substituent defined or exemplified in I presented. When any A is heterocyclyl, this heterocyclic includes any heterocyclyl defined or exemplified herein. When any A is heterocyclic substituted, this heterocyclyl is any heterocyclyl defined or exemplified herein, substituted with one or more of any substitute defined or exemplified herein. In yet another embodiment of the compounds of formula I, each A is H, and each p is 0. In yet another embodiment of the compounds of formula I, each A is substituted or unsubstituted alkyl, wherein alkyl is any alkyl defined or exemplified herein, and, when present, substituents on this alkyl include one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, each A is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and, when present, substituents on this aryl include one or more of any substituents defined or exemplified herein. In a particular embodiment, A is phenyl. In yet another embodiment of the compounds of formula I, each A is substituted or unsubstituted heterocyclyl, wherein heterocycly is any heterocyclic defined or exemplified herein, and, when present, substituents on this heterocyclyl include one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of formula I, one A is H and the other A is substituted or unsubstituted alkyl, wherein alkyl is any alkyl defined or exemplified herein, and, when present, the substituent on this Alkyl includes one or more of any substituent defined or exemplified herein. In yet another embodiment of the compounds of formula I, one A is H and the other A is substituted or unsubstituted aryl, wherein ary is any defined or exemplified aryl herein, and the substituents on this aryl are any substituents defined and exemplified herein. In a particular embodiment, an A is phenyl. In yet another embodiment of the compounds of the formula I, one A is H and the other A is substituted or unsubstituted heterocyclyl, wherein heterocyclyl is any heterocyclyl defined or exemplified herein, and, when present, the substituents on this heterocyclyl include one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, an A is substituted or unsubstituted alkyl, and the other A is substituted or unsubstituted aryl, wherein alkyl and aryl are any alkyl or aryl defined or exemplified in the present, and, when present, the substituents on this alkylaryl or aryl include no or more than any substituents defined or exemplified herein.
In yet another embodiment of the compounds of formula I, an A is substituted or unsubstituted alkyl, and the other A is substituted or unsubstituted heterocyclyl, wherein alkyl and heterocyclyl are any alkyl or heterocyclyl defined or exemplified herein, and, when are present, substituents on this alkyl or heterocyclyl include one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, an A is substituted or unsubstituted aryl, and the other A is substituted or unsubstituted heterocyclyl, wherein aryl and heterocyclyl are any aryl or heterocyclyl defined or exemplified herein, and, when are present, substituents on this aryl or heterocyclyl include one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, Z1 is -O- or -N (R7) -. When Z1 is -N (R7) -, R7 is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or heterocyclyl substituted are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein. In yet another embodiment of the compounds of the formula I, Z2 is -O- or -N (R7) -. When Z2 is -N (R7) -, R7 is H, alkyl, alkyl substituted, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein. In still another embodiment of the compounds of the formula I, Z1 and Z2 are equal, for example, Z1 and Z2 are both -O-, or Z1 and Z2 are both -N (R7) -, where R7 is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl,. substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein. In yet another embodiment of the compounds of the formula I, Z1 and Z2 are different, for example, Z1 is -O- and Z2 is -N (R7) -, Z1 is -N (R7) - and Z2 is -O- , or Z1 and Z2 are both -N (R7) - but in Z1 the R7 is different from the R7 in Z2. When Z1 or Z2 is -N (R7) -, R7 is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein. In still another embodiment of the compounds of formula I, Y is heterocyclyl or heterocyclyl-alkyl, wherein heterocyclyl and heterocyclyl-alkyl are any heterocyclyl or heterocyclyl-alkyl defined or exemplified herein. In a particular embodiment, Y is heterocyclyl-alkyl, for example, thiazolyl-methyl (-CHz-thiazolyl). In still another embodiment of the compounds of formula I, X is heterocyclyl or heterocyclyl-alkyl, wherein heterocyclyl and heterocyclyl-alkyl are any heterocyclyl or heterocyclyl-alkyl defined or exemplified herein. In a particular embodiment, X is heterocyclyl-alkyl, for example, thiazolyl-methyl. In yet another embodiment of the compounds of the formula I, X and Y are different, for example, X and Y are different heterocyclyls, X and Y are different heterocyclyl-alkyl, X is heterocyclyl and Y is heterocyclyl-alkyl, or X is heterocyclyl-alkyl and Y is heterocyclyl, wherein heterocyclyl and heterocyclyl-alkyl are any heterocyclyl or heterocyclyl-alkyl defined or exemplified herein. In yet another embodiment of the compounds of formula I, X and Y are the same. In a particular embodiment, both X and Y are heterocyclyl-alkyls, for example, thiazolyl-methyl. In yet another embodiment of the compounds of the formula I, each Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein the aryl or heteroaryl is any aryl or heteroaryl defined or exemplified herein, and, when present, Substituents on the aryl or heteroaryl include one or more of any substituents defined or exemplified herein.
In still another embodiment of the compounds of the formula I, each Ar is the same, for example, each Ar is an aryl such as phenyl. In yet another embodiment of the compounds of the formula I, each Ar is different, for example, one Ar is a substituted or unsubstituted aryl and the other Ar is a substituted or unsubstituted heteroaryl, each Ar is a different substituted or unsubstituted aryl, or each Ar is a different substituted or unsubstituted heteroaryl, wherein aryl and heteroaryl are any aryl or heteroaryl defined or exemplified herein, and, when present, substituents on the aryl or heteroaryl include one or more of any defined or exemplified substituents at the moment. In yet another embodiment of the compounds of formula I, R1, R3, and R5 are each independently H, alkyl, or substituted alkyl, wherein alkyl and substituted alkyl include any of the alkyl or substituted alkyls defined or disclosed in the present. In still another embodiment of the compounds of the formula I, R1, R3, and R5 are each the same. In a particular embodiment, R1, R3, and R5 are each H. In another particular embodiment R1, R3, and R5 are each alkyl, for example, one of the alkyl groups defined or disclosed herein. In yet another embodiment of the compounds of the formula I, R1, R3, and R5 are each different. In still another embodiment of the compounds of formula I, one of R1, R3, and R5 is different from the other two groups. In still another embodiment of the compounds of formula I, n and m are both 1, and each R 2 is independently H, alkyl, substituted alkyl, aryl-heteroalkyl, aryl-alkyl, or heterocyclyl-alkyl, wherein alkyl, substituted alkyl, aryl -heteroalkyl, aryl-alkyl, or heterocyclyl-alkyl is any alkyl, substituted alkyl, aryl-heteroalkyl, aryl-alkyl, or heterocyclyl-alkyl defined or disclosed herein. In yet another embodiment of the compounds of the formula I, n and m are both 1, and R2 is H. In yet another embodiment of the compounds of the formula I, n is 1, m is 2, and R2 is H. In yet another modality of the compounds of the formula I, n and m are both 1, and at least one R2 is alkyl. In a particular embodiment, at least one R2 is methyl. In another particular embodiment, at least one R2 is ethyl. In another particular embodiment, at least one R 2 is isopropyl. In another particular embodiment, at least one R2 is terbutium. In another particular embodiment, one R2 is H, and the other R2 is methyl. In another particular embodiment, one R2 is H, and the other R2 is ethyl. In another particular embodiment, one R2 is H, and the other R2 is isopropyl. In another particular embodiment, one R2 is H, and the other R2 is terbutium. In yet another embodiment of the compounds of the formula I, n and m are both 1, and R2 is substituted alkyl. In a particular embodiment, at least one R 2 is -CH (CH 3) OH or -CH (CH 3) 0 (t-Bu). In still another embodiment of the compounds of the formula I, n and m are both 1, and at least one R 2 is aryl-heteroalkyl. In a particular embodiment, n and m are both 1, and at least one R 2 is selected from the group consisting of H, methyl, ethyl, benzyl-0-CH 2 -, isopropyl, -CH (CH 3) OBn, -CH 2 CH (CH 3) ) -0-tBu, -CH (CH3) OH, -CH2OH, -CH2OtBu, -CH2CH2NH2, -CH2CH2NH-P (wherein P is a protecting group, such as Boc, Ac, methanesulfonyl, etc.), - CH2CH2-morpholine, -CH2C (0) OH, -CH2C (0) OtBu, and -CH2C (0) -NH2. In still another embodiment of the compounds of the formula I, n and m are both 1, and at least one R 2 is aryl-heteroalkyl. In a particular embodiment, n and m are both 1, an R 2 is H, and an R 2 is selected from the group consisting of H, methyl, ethyl, benzyl-0-CH 2 -, isopropyl, -CH (CH 3) OBn, - CH2CH (CH3) -0-tBu, CH (CH3) OH, -CH2OH, -CH2OtBu, -CH2CH2NH2, -CH2CH2NH-P (wherein P is a protecting group, such as Boc, Ac, methanesulfonyl, etc.) , -CH2CH2-morpholine, -CH2C (0) OH, -CH2C (0) OtBu, and -CH2C (0) -NH2. In yet another embodiment of the compounds of formula I, R 4 is H, alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substituted alkyl, and heteroalkyl are any alkyl, substituted alkyl, and heteroalkyl defined or disclosed herein . In a particular embodiment, R4 is H.
In yet another embodiment of the compounds of formula I, R6 is H, alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substituted alkyl, and heteroalkyl are any alkyl, substituted alkyl, and heteroalkyl defined or disclosed herein . In a particular embodiment, R6 is H. In yet another embodiment of the compounds of formula I, R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl , substituted aryl, heterocyclyl, substituted heterocyclyl, and -CN, wherein, when R8 or R9 are alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl, this alkyl, substituted alkyl, halogen, aryl, aryl substituted, heterocyclyl, substituted heterocyclyl are any of these defined or disclosed groups herein. In still another embodiment of the compounds of the formula I, R8 and R9 are the same. In a particular embodiment, R8 and R9 are both H. In yet another embodiment of the compounds of the formula I, R8 and R9 are different. In a particular embodiment, R8 is alkyl and R9 is H. In another particular embodiment, R8 is isopropyl and R9 is H. In yet another embodiment of the compounds of formula I, at least one of the -L3-A- fractions (L -Ar) P is an -alkylene-aryl group, wherein these alkylene and aryl moieties are any defined alkylene and aryl moieties or exemplified herein, optionally substituted on the alkyl and / or aryl with one or more of any substitutes defined or exemplified herein. In yet another embodiment of the compounds of formula I, at least one of the fractions of - L3-A- (L4-Ar) p is a -alkyl-aryl-alkylene-aryl group, wherein these alkyl fractions i and aryl are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl with one or more of any substitutents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-aryl-alkylene-heteroaryl group, wherein these alkylene, aryl moieties , and heteroaryl are any alkyl, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the fractions of -L3-A- (L4-Ar) P is a -alkyl-heteroaryl-alkylene-heteroaryl group, wherein these alkylene and heteroaryl fractions are any alkylene and heteroaryl moieties defined or exemplified herein, optionally substituted on the non-and / or heteroaryl alkyl with one or more of any substituents defined or exemplified herein.
In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) P moieties is an -alkylene-heteroaryl-alkylene-aryl group, wherein these alkylene, aryl moieties , and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-aryl-aryl group, wherein these alkylene and aryl fractions are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-aryl-O-aryl group, wherein these alkylene and aryl fractions are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-aryl-CH2-0-aryl group, wherein these alkylene moieties Y aryl are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkyl and / or aryl with one or more of any constituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is a -alkyl-aryl-OCH2-aryl group, wherein these alkylene and aryl are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl with one or more of any constituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-aryl-N H -aryl group, wherein these alkyl fractions no and aryl are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl with one or more of any constituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the fractions of -L3-A- (L4-Ar) p is a -alkyl-aryl-heterocyclyl group, wherein these fraction is alkylene , aryl, and heterocyclyl are any alkyl, aryl, and heterocyclyl fractions defined or exemplified herein, optionally substituted on the non-and / or aryl and / or heterocyclyl alkyl with one or more of any defined substituents or exemplified in the I presented. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L-Ar) p fractions is an -alkylene-aryl-O-ethercyclyl group, wherein these alkylene moieties, aryl, and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein . In still another embodiment of the compounds of formula I, at least one of the fractions of -L3-A- (L4-Ar) p is an -alkylene-aryl-CH2-0-heterocyclyl group, wherein these fractions of alkylene, aryl, and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified in the present, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is a -alkyl-aryl-OCH2-heterocyclyl group, wherein these alkylene moieties , aryl, and heterocyclyl are any alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein .
In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-aryl-NH-heterocyclyl group, wherein these alkylene, aryl fractions , and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L -Ar) p fractions is an -alkylene-heterocyclyl-aryl group, wherein these alkylene, aryl, and heterocyclyl are any "alkylene, aryl, and heterocyclyl" moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. of the compounds of formula I, at least one of the fractions of -L3-A- (L4-Ar) p is an -alkylene-heterocyclyl-O-aryl group, wherein these alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. mode of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-heterocyclyl-CH2-0-aryl group, wherein these alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl moieties , and heterocyclyl defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-heterocyclyl-OCH2-aryl group, wherein these alkylene, aryl fractions , and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-heterocyclyl-NH-aryl group, wherein these alkylene, aryl moieties , and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is a group -alkyl-heterocyclyl-heterocyclyl, wherein these alkylene, aryl, and heterocyclyl moieties are any alkyl, aryl, and heterocyclyl fractions defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-heterocyclyl-heterocyclyl group, wherein these alkylene, aryl, and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-heterocyclyl-CH2-0-heterocyclyl group, wherein these alkylene, aryl, and heterocyclyl moieties are any alkylene moieties, aryl, and heterocyclyl defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the fractions of -L3-A- (L4-Ar) p is a group -alkylene-heterocyclyl-OCH2-heterocyclyl, wherein these fractions of alkylene, aryl, and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein . In still another embodiment of the compounds of formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-heterocyclyl-NH-heterocyclyl group, wherein these alkylene, aryl moieties , and heterocyclyl are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heterocyclyl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-aryl-heteroaryl group, wherein these alkylene, aryl, and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-aryl-O-heteroaryl group, wherein these alkylene, aryl moieties , and heteroaryl are any alkylene, aryl, and heteroaryl defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, when at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-aryl-CH2-0-heteroaryl group, wherein these fractions of alkylene, aryl, and heteroaryl are any alkylene, aryl, and heteroaryl moieties as defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified in the present . In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L -Ar) p fractions is an -alkylene-aryl-OCH2-heteroaryl group, wherein these alkylene moieties, aryl, and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In yet another modality of the compounds of the formula I, at least one of the fractions of -L3-A- (L4-Ar) p is a group -alkyl-aryl-NH-heteroaryl, wherein Alkylene, aryl, and heteroaryl fractions are any alkyl, aryl, and heteroaryl moieties defined or exemplified in present, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-heteroaryl-aryl group, wherein these alkylenyl, aryl, and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the fractions of -L3-A- (L4-Ar) p is a -alkyl-heteroaryl-O-aryl group, wherein these fractions of Alkyl, aryl, and heteroaryl are any alkylenal moieties, aryl, and heteroaryl defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In yet another modality of the compounds of formula I, at least one of the fractions of -L3-A- (L4-Ar) p is a -alkyl-heteroaryl-CH2-0-aryl group, wherein these alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of formula I, at least one of the -L3-A- (L4-Ar) p fractions is a -alkyl-heteroaryl-OCH2-aryl group, wherein these fractions of Alkylene, aryl, and heteroaryl are any alkylene, aryl, and heteroaryl groups defined or exemplified herein, optionally substituted on the alkyl and / or aryl and / or heteroaryl with one or more of any defined substitutes or exemplified in the present. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an -alkylene-heteroaryl-N H -aryl group, wherein these fractions of alkylene, aryl, and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified in I presented . In still another embodiment of the compounds of Formula I, at least one of the fractions of -L3-A- (L4-Ar) p is a -alkyl-hete-rocyclyl-heteroaryl group, wherein these alkylene moieties , aryl, and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any defined substituents or exemplified in the present. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L -Ar) p fractions is an -alkylene-heterocyclyl-O-heteroaryl group, wherein these alkylene, aryl fractions , and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In still another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-heterocyclyl-CH2-0-heteroaryl group, wherein these alkylene moieties , aryl, and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-heteroaryl-OCH2-heteroaryl group, wherein these alkylene, aryl moieties , and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein.
In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p moieties is an -alkylene-heteroaryl-NH-heteroaryl group, wherein these alkylene, aryl moieties , and heteroaryl are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and / or aryl and / or heteroaryl with one or more of any substituents defined or exemplified herein. In yet another embodiment of the compounds of the formula I, at least one of the -L3-A- (L4-Ar) p fractions is an alkyl group. In still another embodiment of the compounds of the formula I, both -L3-A- (L4-Ar) p moieties are alkyl groups, wherein the alkyl groups are identical or different. In still another embodiment of the compounds of the formula I, both the -L3-A- (L4-Ar) p moieties are -CH2-phenyl, and X and Y are both -CH2-heterocyclyl. In still another embodiment of the compounds of formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and Y is -CH2-heterocyclyl. In still another embodiment of the compounds of the formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and X is -CH2-heterocyclyl. In yet another embodiment of the compounds of formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and Y is -CH2- thiazolyl. In yet another embodiment of the compounds of the formula I, both fractions of -L3-A- (L-Ar) p are -CH2-phenyl, and X is -CH2-thiazolyl. In yet another embodiment of the compounds of the formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, and ym are both 1. In still another embodiment of the compounds of the formula I, both fractions of -L3-A- (l_4-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, ynym are both 1, and at least one R2 is an alkyl of 1 to 6 carbon atoms. In still another embodiment of the compounds of formula I, both fractions of -L3-A- (L-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, ynym are both 1, and when minus one R 2 is a hydroxy alkyl of 1 to 6 carbon atoms. In still another embodiment of the compounds of formula I, both fractions of -L3-A- (L-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, ynym are both 1, and when less one R2 is an alkoxy of 2 to 10 carbon atoms-alkyl. In still another embodiment of the compounds of the formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, ynym are both 1, and when minus one R 2 is an aryl-alkyloxy of 7 to 14 carbon atoms-alkyl. In still another embodiment of the compounds of formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, and n and m are both 1, and at least one R2 is an amino-alkyl of 1 to 6 carbon atoms. In still another embodiment of the compounds of the formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, ynym are both 1, and when minus one R 2 is an amino-alkyl of 1 to 6 carbon atoms substituted on the nitrogen atom with an amine protecting group selected from acyl, alkyl-sulfonyl, aryl-sulfonyl, heterocyclyl-acyl, and benzyl. In still another embodiment of the compounds of the formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, ynym are both 1, and when minus one R 2 is a substituted or unsubstituted heterocyclyl-alkyl. In still another embodiment of the compounds of formula I, both fractions of -L3-A- (L4-Ar) p are -CH2-phenyl, and X and Y are both -CH2-thiazolyl, ynym are both 1, and L2 is -CH2-. In yet another embodiment of the compounds of the formula I, at least one moiety of -L3-A- (L4-Ar) p is -CH2-phenyl-CH2-phenyl. In still another embodiment of the compounds of formula I, at least one moiety of -L3-A- (L4-Ar) p is -CH2-heteroaryl-CH2-phenyl. In yet another embodiment of the compounds of formula I, at least one moiety of -L3-A- (L4-Ar) p is -CH2-phenyl-CH2-heteroaryl.
In yet another embodiment of the compounds of formula I, at least one moiety of -L3-A- (L4-Ar) p is -CH2-heteroaryl-CH2-heteroaryl. In yet another embodiment of the compounds of formula I, X and Y are both heterocyclyl-alkyl. In still another embodiment of the compounds of formula I, X and Y are both heteroaryl-alkyl. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, and both -L3-A- (L4-Ar) p groups are substituted or unsubstituted benzyl. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, and L2 is -CH2-. In another embodiment of the compounds of formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, and m and n they are both 1. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L -Ar) p are substituted or unsubstituted benzyl, L2 is - CH2-, m and n are both 1, and R1 is H. In another embodiment of the compounds of formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L -Ar) p they are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R is H, and Z1 is -N- (alkyl) -. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, and Z1 is -N (CH3) -. In another embodiment of the compounds of formula I, L is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn they are both 1, R1 is H, Z is -N- (alkyl) -, and Z2 is -O-. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn they are both 1, R1 is H, Z1 is -N (CH3) -, and Z2 is -O-. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L -Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, m and n they are both 1, R1 is H, Z1 is -N- (alkyl) -, Z2 is -O-, and Y is -CH2-4-substituted or unsubstituted thiazole. In another embodiment of the compounds of formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L -Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, m and n they are both 1, R1 is H, Z1 is -N- (alkyl) -, Z2 is -O-, and R8-Y is -CH2- (2-alkyl-4-thiazole). In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R is H, Z is -N- (H) -, Z2 is -O-, and R8-Y is -CH2- (2-iPr-4-thiazole). In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are benzyl substituted or unsubstituted, L2 is -CH2-, m and n are both 1, R1 is H, Z1 is -N- (alkyl) -, Z2 is -O-, Y is -CH2-4-substituted or unsubstituted thiazole, and X is -CH2 -5-substituted or unsubstituted thiazole. In another embodiment of the compounds of formula I, L is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn both are 1, R1 is H, Z1 is -N- (alkyl) -, Z2 is -O-, Y is -CH2-4-substituted or unsubstituted thiazole, and X is unsubstituted -CH2-5-thiazole. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn they are both 1, R1 is H, Z is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), and X is -CH2-5-thiazole unsubstituted In another embodiment of the compounds of the formula I, each R2 is independently H or idroxy-alkyl. In another embodiment of the compounds of the formula I, each R2 is independently H or heterocyclyl-alkyl. In another embodiment of the compounds of formula I, each R2 is independently H or -CH2-heterocyclyl, wherein this heterocyclyl is a 5- or 6-membered ring, having at least one ring nitrogen atom. In another embodiment of the compounds of formula I, each R2 is independently H or -CH2-heterocyclyl, wherein this heterocyclyl is a 6-membered ring, having at least one ring nitrogen atom.
In another embodiment of the compounds of formula I, each R2 is independently H or -CH2-heterocyclyl, wherein this heterocyclyl is a 6-membered ring, having at least one ring nitrogen atom, wherein the fraction of - CH2- thereof is linked to the ring nitrogen atom. In another embodiment of the compounds of the formula I, each R2 is independently H or -CH2-heterocyclyl, wherein this heterocyclyl is selected from the group consisting of piperadyl, piperazyl, and morpholinyl. In another embodiment of the compounds of the formula I, each R2 is independently H or -CH2-heterocyclyl, wherein this heterocyclyl is selected from the group consisting of piperadyl, piperazyl, and morpholinyl, and the -CH2- fraction of the The same is linked to a nitrogen atom of the heterocyclyl ring. In another embodiment of the compounds of the formula I, each R2 is independently H or amino-alkyl. In another embodiment of the compounds of the formula I, each R 2 is independently H or amino-alkyl substituted with an amine protecting group selected from the group consisting of acetyl, alkyl-sulfonyl, Boc, Cbz, and Fmoc. In another embodiment of the compounds of formula I, each R2 is independently H or ethyl acetamide (-CH2CH2NHC (0) CH3). In another embodiment of the compounds of formula I, L is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn they are both 1, R1 is H, Z1 is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is unsubstituted -CH2-5-thiazole, and R2 is independently H or hydroxy-alkyl. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, Z is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is -CH2-5-thiazole unsubstituted , and one R2 is H and the other R2 is hydroxy-alkyl. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, Z1 is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is -CH2-5-thiazole unsubstituted , and one R2 is H and the other R2 is hydroxymethyl. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, Z1 is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is -CH2-5-thiazole unsubstituted , and each R2 is independently H or -CH2-heterocyclyl, wherein this heterocyclyl is a 5- or 6-membered ring having at least one ring nitrogen atom. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, Z1 is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is unsubstituted -CH2-5-thiazole, and each R2 is independently H or -CH2-heterocyclyl, wherein this heterocyclyl is selected from the group that it consists of piperadyl, piperazyl, and morpholinyl, and the -CH2-moiety thereof is bonded with a nitrogen atom of the heterocyclyl ring. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, Z1 is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is -CH2-5-thiazole unsubstituted , and one R2 is H and the other R2 is -CH2-heterocyclyl, wherein this heterocyclyl is selected from the group consisting of piperadyl, piperazyl, and morpholinyl, and the -CH2- fraction thereof is bonded to a nitrogen of the heterocyclyl ring.
In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, Z1 is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is -CH2-5-thiazole unsubstituted , and each R2 is independently H or amino-alkyl substituted with an amine protecting group selected from the group consisting of acetyl, alkyl-sulfonyl, Boc, Cbz, and Fmoc. In another embodiment of the compounds of the formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn are both 1, R1 is H, Z1 is -N- (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is -CH2-5-thiazole unsubstituted , and one R2 is H and the other R2 is amino-alkyl substituted with an amine protecting group selected from the group consisting of acetyl, alkyl-sulfonyl, Boc, Cbz, and Fmoc.
In another embodiment of the compounds of Formula I, L1 is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn they are both 1, R1 is H, Z1 is -N (H) -, Z2 is -O-, R8-Y is -CH2- (2-iPr-4-thiazole), X is unsubstituted -CH2-5-thiazole, and one R2 is H and the other R2 is ethyl acetamide (-CH2CH2NHC (0) CH3). In another embodiment of the compounds of Formula I, L is -C (O) -, R4 is H, both groups -L3-A- (L4-Ar) p are substituted or unsubstituted benzyl, L2 is -CH2-, myn they are both 1, R1 is H, Z1 is -N (alkyl) -, Z2 is O-, and Y is -CH2-thiazole substituted or unsubstituted. In still another embodiment, the compounds of Formula I, or the pharmaceutically acceptable salts, solvates, esters, or stereoisomers thereof, have the structure shown in the Formula HA: Formula NA wherein R 11 and R 16 are each independently heterocyclyl, or substituted heterocyclyl; and R12, R3, R14, and R15 are each independently H, -alkyl of 1 to 4 carbon atoms, or -alkyl of 1 to 4 substituted carbon atoms. In yet another embodiment of the compounds of Formula NA, R 3 is H, -alkyl of 1 to 4 carbon atoms, - (CH 2) 0. ! CR ^ R ^ OR19, - (CH2) o.3CR17R18NR20R21, - (CH2) 0.3CR 7R18NR17C (O) - NR R, - (CH2) 3C (0) R22, Ó - (CHZ), R15 are each independently H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R17 and R18 are each independently H or -alkyl of 1 to 3 carbon atoms; R19 is H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R20 and R21 are each independently H, -alkyl of 1 to 3 carbon atoms, -C (0) R17 or -S (0) 2R17; or Rz and R21, taken together with the nitrogen atom to which they are attached, form an unsubstituted or substituted 5- to 6-membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O; R22 is H, -alkyl of 1 to 3 carbon atoms, -OR19, or -NR20R21; or R23 is an unsubstituted or substituted 5- to 6-membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O. In yet another embodiment of the compounds of Formula NA, R13 is - ( CH2) o.3CR17R18NR20R21, - (CH2) 0.3CR17R18NR17C (O) -NR20R21, or - (CHzILa-R23, where R20 and R21 form a 5-6 membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from of the group consisting of N and O, or R23 is an unsubstituted or substituted 5- to 6-membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O, and the heterocyclyl ring of 5 to 6 members is optionally substituted with an alkyl of 1 to 2 carbon atoms In yet another embodiment of the compounds of Formula NA, R 13 is - (CH 2) 0-iCR 17 R 18 OR 19. In a particular embodiment, R 13 is a hydroxy-alkyl of 1 to 2 carbon atoms, or an alkoxy-alkyl group of 1 to 6 carbon atoms. In still another embodiment of the compounds of Formula NA, R 13 is - (CH 2) or 3CR 17 R 18 NR 20 R 21. In a particular embodiment, R 13 is an alkylene group of 1 to 4 carbon atoms-NH 2, alkylene of 1 to 4 carbon atoms-NHP (wherein P is a protecting group, such as a group Boc, Fmoc, Cbz, Ac , trifluoro-acetyl, toluene-sulfonyl, benzyl, etc.). or an alkylene group of 1 to 4 carbon atoms-N- (alkyl) 2. In yet another embodiment of the compounds of the Formula HA, R13 is - (CH2) o.3CR17R18NR17C (0) -NR20R21. In a particular embodiment, R 13 is an alkylene group of 1 to 4 carbon atoms-C (0) NH 2, or an alkylene group of 1 to 4 carbon atoms-C (0) N- (alkyl) 2. In yet another embodiment of the compounds of the Formula NA, R11, R12, R13, R14, R15, and R16 are each independently selected from the groups shown in the following Table: In yet another embodiment of the compounds of Formula HA, R1 is substituted or unsubstituted heterocyclyl, R12 is alkyl, R13 is substituted or unsubstituted heterocyclyl-alkyl, R14 and R15 are each independently substituted or unsubstituted aryl-alkyl, and R16 is heterocyclic substituted or unsubstituted. In yet another embodiment of the compounds of Formula NA, R 11 is substituted heterocyclic, R 12 is alkyl, R 13 is unsubstituted heterocyclyl-alkyl, R 14 and R 15 are both unsubstituted aryl-alkyl, and R 16 is unsubstituted heterocyclyl. In yet another embodiment of the compounds of Formula HA, R 11 is substituted or unsubstituted heterocyclic, R 12 is alkyl, R 13 is hydroxy alkyl, R 14 and R 15 are each independently substituted or unsubstituted alkyl aryl, and R 16 is substituted or unsubstituted heterocyclic. . In yet another embodiment of the compounds of Formula HA, R 11 is substituted heterocyclic, R 12 is alkyl, R 13 is hydroxy alkyl, R 14 and R 15 are both unsubstituted aryl alkyl, and R 16 is unsubstituted heterocyclyl. In yet another embodiment of the compounds of the Formula HA, R 11 is substituted or unsubstituted heterocyclic, R 12 is alkyl, R 13 is protected or unprotected amino-alkyl, R 14 and R 15 are each independently substituted or unsubstituted alkyl aryl, and R 16 is substituted or unsubstituted heterocyclyl. In yet another embodiment of the compounds of the Formula 11 A, R 11 is substituted heterocyclic, R 12 is alkyl, R 13 is protected amino-alkyl, R 14 and R 5 are both unsubstituted aryl-alkyl, and R 16 is unsubstituted heterocyclyl. In still another embodiment of the compounds of the Formula NA, R1 is substituted heterocyclic, R12 is alkyl, R13 is amino- alkyl acylated, R14 and R15 are both aryl-unsubstituted alkyl, and R16 is unsubstituted heterocyclyl. In another embodiment, the compounds of Formula I, or the pharmaceutically acceptable salts, solvates, stereoisomers, and / or esters thereof, have the following structure IIB: Formula IIB R10a and R10b are each independently H or -alkyl of 1 to 4 carbon atoms; R12 is H or -CH3; R13 is H, -alkyl of 1 to 4 carbon atoms, - (CHzJcCR ^ R ^ OR19, - (CH2) o.3CR17R18NR20R21, - (CH2) 0.3CR17R18NR17C (O) NR20R21, - {CH2) 3C (0 ) fí22, - (CH2) ,. 3S (0) 2R22, or - (CH2) 1 3R23; R 14 and R 15 are each independently H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R 7 and R 18 are each independently H or -alkyl of 1 to 3 carbon atoms; R19 is H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R20 and R21 are each independently H, -alkyl of 1 to 3 carbon atoms, -C (0) R17 or -S (0) 2R17; or R20 and R21, taken together with the nitrogen atom to which they are attached, form an unsubstituted or substituted 5- to 6-membered heterocyclyl ring, containing 1 to 2 heteroatoms selected from the group consisting of N and O; R22 is H, -alkyl of 1 to 3 carbon atoms, -OR19 or -NR 0R21; and R23 is an unsubstituted or substituted 5 or 5 membered heterocyclyl ring, containing 1 to 2 heteroatoms selected from the group consisting of N and O. In yet another embodiment of the compounds of Formula IIB, R13 is - (CH2) 0.3CR17R18NR20R21, - (CH2) 0.3CR17R18N R17C (0) -NR20R21, or - (CH2) i.3-R23, wherein R20 and R21 form a 5-6 membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O, or R23 is an unsubstituted or substituted 5- to 6-membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N y, O, and the 5- to 6-membered heterocyclyl ring is optionally substituted with an alkyl of 1 to 2 carbon atoms.
In another embodiment, the compounds of Formula I, or the pharmaceutically acceptable salts, solvates, stereoisomers, and / or esters thereof, have the following IIC structure: Formula IIC wherein: R13 is H, -alkyl of 1 to 4 carbon atoms, - (CH2) 0-iCR17R18OR19, - (CH2) 0.3CR17R 8NR20R2 \ - (CH2) or- 3CR17R18NR17C (O) NR20R21, - (CH2 ) 1.3C (0) R22, or - (CH2) 1.3R23; R 7 and R 18 are each independently H or alkyl of 1 to 3 carbon atoms carbon; R19 is H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R20 and R21 are each independently H, -alkyl of 1 to 3 carbon atoms, -C (0) R17, or -S (0) 2R17; or R20 and R2, taken together with the nitrogen atom to which they are attached, form a 5-6 membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O; R22 is H, -alkyl of 1 to 3 carbon atoms, -OR19, or -NR 0R21; and R23 is a 5-6 membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O. In yet another embodiment of the compounds of Formula IIC, R13 is - (CH2) 0 -3CR17R18NR20R21, - (CH2) 0.3CR17R18NR 7C (O) -NR20R21, or - (CH2), 3R23, wherein R20 and R21 form a 5-6 membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from of the group consisting of N and O, or R23 is an unsubstituted or substituted 5- to 6-membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O, and the heterocyclyl ring of to 6 members is optionally substituted with an alkyl of 1 to 2 carbon atoms. In yet another embodiment of the compounds of the Formula IIC, R13 is - (CH2) o.3CR17R18NR20R21. In yet another particular embodiment, R 3 is an alkylene group of 1 to 4 carbon atoms - NH 2, alkylene of 1 to 4 carbon atoms - NHP (wherein P is a protecting group, such as Boc, Fmoc, Cbz, Ac , trifluoroacetyl, a toluene sulfonyl group, benzyl, etc.), or an alkylene group of 1 to 4 carbon-N (alkyl) atoms 2. In yet another embodiment of the compounds of Formula IIC, R13 is - (CH2) 0.3CR17R, 8NR17C (O) -NR20R21. In a particular embodiment, R 13 is an alkylene group of 1 to 4 carbon atoms-C (0) NH 2, or an alkylene group of 1 to 4 carbon atoms-C (0) N (alkyl) 2. In yet another embodiment of the compounds of Formula IIC, R13 is -CH2OH, -CH2CH2NHC (0) CH3, or In another embodiment, the compounds of the present invention, or the pharmaceutically acceptable salts, solvates, stereoisomers, and / or esters thereof, have the following IID structure: Formula IID wherein: L1 is selected from the group consisting of -C (R6) 2-, - C (O) -, -S (0) 2-, -N (R7) -C (0) -, I co)-; each L3 is independently a covalent bond, an alkylene, or a substituted alkylene; each L4 is independently selected from the group which consists of a covalent bond, alkylene, substituted alkylene, -O-, -CH2-0-, and -NH-; each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl, with the proviso that when A is H, P is 0; Z1 and Z * are each independently -O- or -N (R7) -; Y and X are independently selected from the group consisting of heterocyclyl and heterocyclyl-alkyl; each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R1, R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl-alkyl, and substituted aryl-alkyl; R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxy-alkyl, hydroxy-alkyl, aryl-heteroalkyl, substituted aryl-heteroalkyl, aryl-alkyl, substituted aryl-alkyl, heterocyclyl-alkyl, heterocyclyl- substituted alkyl, amino-alkyl, amino-substituted alkyl, -alkylene-C (O) -OH, -alkylene-C (0) -0-alkyl, -alkylene-C (0) -amino, -alkylene-C (0) )-I rent; R4 and R6 is independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; each R7 is independently selected from the group which consists of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, substituted aryl, heterocyclyl, substituted heterocyclyl, and -CN; and each p is independently 0 or 1. In another embodiment of the compounds of Formula IID, L1 is -C (R6) 2-. In another embodiment of the compounds of Formula IID, L1 is -CH2-. In another embodiment of the compounds of Formula IID, each L3 is alkylene. In another embodiment of the compounds of the Formula IID, each L3 is -CH2-. In another embodiment of the compounds of Formula IID, each A is aryl or substituted aryl. In another embodiment of the compounds of Formula IID, each A is phenyl or substituted phenyl. In another embodiment of the compounds of Formula IID, X is heterocyclyl-alkyl. In another embodiment of the compounds of Formula IID, X is thiazolyl-methyl. In another embodiment of the compounds of the Formula IID, Y is heterocyclyl-alkyl. In another embodiment of the compounds of Formula IID, Y is thiazolyl-methyl. In another embodiment of the compounds of Formula IID, Z1 is -N (R7) -. In another embodiment of the compounds of the Formula IID, Z1 is -NH-. In another embodiment of the compounds of Formula IID, Z1 is -N (alkyl) -. In another embodiment of the compounds of the Formula IID, Z1 is -N (CH3) -. In another embodiment of the compounds of the Formula IID, Z2 is -OR-. In another embodiment of the compounds of Formula IID, L1 is -C (F6) 2-, and X and Y are heterocyclyl-alkyl. In another embodiment of the compounds of Formula IID, L1 is -CH2-, and X and Y are heterocyclyl-alkyl. In another embodiment of the compounds of Formula IID, L1 is -CH2-, and X and Y are thiazolyl-methyl. In another embodiment of the compounds of the Formula IID, L1 is -C (R6) 2-, and Z1 is -N (F7) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, and Z1 is -N (R7) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, and Z1 is -NH-.
In another embodiment of the compounds of Formula IID, L1 is -CH2-, and Z1 is -N (alkyl) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, and Z1 is -N (CH3) -. In another embodiment of the compounds of Formula IID, L1 is -C (R6) 2-, and Z2 is -O-. In another embodiment of the compounds of Formula IID, each L3 is alkylene, and each A is aryl or substituted aryl. In another embodiment of the compounds of Formula IID, each L3 is -CH2-, and each A is aryl or substituted aryl. In another embodiment of the compounds of the Formula IID, each L3-A is benzyl or substituted benzyl. In another embodiment of the compounds of Formula IID, X and Y are heterocyclyl-alkyl, and Z1 is -N (R7) -. In another embodiment of the compounds of Formula IID, X and Y are thiazolyl-methyl, and Z1 is -N (R7) -. In another embodiment of the compounds of Formula IID, X and Y are thiazolyl-methyl, and Z 1 is -N (alkyl) -. In another embodiment of the compounds of Formula IID, X and Y are thiazolyl-methyl, and Z1 is -N (CH3) -. In another embodiment of the compounds of Formula IID, X and Y are thiazolyl-methyl, and Z 1 is -NH-. In another embodiment of the compounds of Formula IID, X and Y are heterocyclyl-alkyl, and Z1 is -O-. In another embodiment of the compounds of Formula IID, X and Y they are thiazolyl-methyl, and Z2 is -O-. In another embodiment of the compounds of Formula IID, Z1 is -N (R7) -, and Z2 is -O-. In another embodiment of the compounds of Formula IID, Z1 is -N (alkyl) -, and Z2 is -O-. In another embodiment of the compounds of Formula IID, Z1 is -N (CH3) -, and Z3 is -O-. In another embodiment of the compounds of Formula IID, Z1 is -NH-, and Z2 is -O-. In another embodiment of the compounds of Formula IID, L1 is -C (R6) 2, X and Y are heterocyclyl-alkyl, and Z1 is -N (R7) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, X and Y are heterocyclyl-alkyl, and Z1 is -N (R7) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, X and Y are thiazolyl-methyl, and Z1 is -N (R7) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, X and Y are thiazolyl-methyl, and Z1 is -N (alkyl) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, X and Y are thiazolyl-methyl, and Z1 is -N (CH3) -. In another embodiment of the compounds of Formula IID, L1 is -CH2-, X and Y are thiazolyl-methyl, and Z is -NH-. In another embodiment of the compounds of Formula IID, L1 is -C (R6) 2-, X and Y are heterocyclyl-alkyl; and Z2 is -O-. In another embodiment of the compounds of Formula IID, L1 is -CH2-; X and Y are heterocyclyl-alkyl; and Z2 is -O-.
In another embodiment of the compounds of Formula IID, L1 is -CH2-; X and Y are thiazolyl-methyl; and Z2 is -O-. In another embodiment of the compounds of Formula IID, L1 is -C (R6) 2-; each L3 is alkylene; each A is aryl or substituted aryl; X and Y are heterocyclyl-alkyl; Z is -N (R7) -; and Z1 is -O-. In another embodiment of the compounds of Formula IID, L1 is -CH2-; each L3-A is benzyl, or substituted benzyl; X and Y are thiazolyl-methyl; Z1 is -N (CH3) -; and Z2 is -O-. In another embodiment of the compounds of Formula IID, L1 is -CH2-; each L3-A is benzyl, or substituted benzyl; Z1 is -N (CH3) -; Z2 is -O-; X is: In still another embodiment, the compounds of Formula I are named below in a tabular format (Table 6), as the compounds of General Formula II: Formula II The compounds of the General Formula II are illustrated as a "core" (Z) structure substituted with four fractions T1, T2, X1, and X2. The core structures Z are illustrated in Table 1. The points of attachment of T1, T2, X1, and X2 are indicated on each of the core structures illustrated in Table 1. Tables 2 to 5, respectively, show the structures of fractions T1, T2, X1, and X2. The point of attachment of the core structure Z is indicated in each of the structures T1, T2, X1, and X2. Each core structure Z in Table 1, and each substitute T1, T2, X1, and X2, and Tables 2 to 5, are represented by a "code" comprising a letter and a number. Each structure of a compound of Formula II can be designated in a tabular form, by combining the "code" representing each structural fraction, using the following syntax: Z.T1.T2.X1.X2. Therefore, for example, Z1.T1 A.T2B.X1 A.X2A represents the following structure: In the structures illustrated in Tables 1 to 5, the term "Alk" means an alkyl, cycloalkyl, or substituted or unsubstituted alkylene group, wherein the terms "alkyl", "cycloalkyl", and "alkylene", are as defined at the moment. "Alk" means an alkyl or cycloalkyl group when illustrated as monovalent, and an alkylene group when illustrated as a divalent. "Het" is a substituted or unsubstituted heterocyclyl or heterocyclylene group, wherein the term "heterocyclyl" is as defined herein, and the term "heterocyclylene" means a heterocyclyl group as defined in present, wherein a hydrogen atom has been replaced by an open valence (in analogy to alkylene), thereby defining a divalent heterocyclyl. "Het" is a heterocyclyl when illustrated as monovalent, and heterocyclylene when illustrated as divalent. "Ar" is a substituted or unsubstituted aryl or arylene group, wherein the term "aryl" is as defined herein, and the term "arylene" means an aryl group as defined herein, wherein an hydrogen has been replaced by an open valence (in analogy to alkylene), thereby defining a divalent aryl. "Ar" is aryl when it is illustrated as monovalent, and arylene when illustrated as divalent. When substituted, "Alk", "Het", and "Ar" may be substituted with any of the substituents defined or exemplified herein. For example, "Alk" substituents may include ether, halogen, -OH, amide, amine, etc .; "Het" substituents may include alkyl, aryl, carbonyl, -OH, halogen; and "Ar" substituents may include alkyl, aryl, -OH, halogen, etc., with the proviso that the resulting structure is chemically reasonable, and compounds that would be sufficiently stable for the formulation in a pharmaceutically acceptable composition would be provided. When a structure or sub-structure shown in the Tables below, contains more than one group "Alk", "Het", or "Ar", these groups are independently selected, and may be equal or different. In this way, for example, each of the "Alk" groups of the sub- structure T1A, are independently selected, and may be the same or different. Table 1: Core Structures Code Core Structure Table 2: Structures T1 Code Structure T1 Table 3: Structures T2 15 Code Structure T2 T2A -O-Alk-Het T2B -NH-Alk-Het T2C -N (Alk) -Alk-Het T2D -N (Alk) -Het 20 Table 4: Structures X1 Code Structure X1 X1A -Alk X1B -Alk-Ar X1C -Alk-Het 25 X1D -Alk-Ar-O-Alk-Ar X1E -Alk-Ar-O- • Alk-Het Table 5: Structures X2 Code Structure X2 X2A -Alk X2B -Alk-Ar X2C -Alk-Het X2D -Alk-Ar-O -Alk-Ar X2E -Alk- Ar-O -Alk-Het Table 6: List of etructures of compounds of the Formula Z1.T1A.T2A.X1A.X2A, Z2.T1A.T2A.X1A.X2A, Z3.T1A.T2A.X1A.X2A, Z4.T1A.T2A.X1A.X2A, Z5.T1A.T2A.X1A.X2A, Z6.T1A.T2A.X1A.X2A, Z1.T1B.T2A.X1A.X2A, Z2.T1B.T2A-X1A.X2A, Z3.T1B.T2A.X1A.X2A, Z4.T1B.T2A.X1A.X2A, Z5.T1B.T2A.X1A.X2A, Z6.T1B.T2A.X1A.X2A, Z1.T1C.T2A.X1A.X2A, Z2.T1C.T2A.X1A.X2A, Z3.T1C.T2A.X1A.X2A, Z4.T1C.T2A.X1A.X2A, Z5.T1C.T2A.X1A.X2A, Z6.T1C.T2A.X1A.X2A, Z1.T1D.T2A.X1A.X2A, Z2.T1D.T2A.X1A.X2A, Z3.T1D.T2A.X1A.X2A, Z4.T1D.T2A.X1A.X2A, Z5.T1D.T2A.X1A.X2A, Z6.T1D.T2A.X1A.X2A, Z1.T1A.T2B.X1A.X2A, Z2.T1A.T2B.X1A.X2A, Z3.T1A.T2B.X1A.X2A, Z4.T1A.T2B.X1A.X2A, Z5.T1A.T2B.X1A.X2A, Z6.T1A.T2B.X1A.X2A, Z1.T1B.T2B.X1A.X2A, Z2.T1B.T2B.X1A.X2A, Z3.T1B.T2B.X1A.X2A, Z4.T1B.T2B.X1A.X2A, Z5.T1B.T2B.X1A.X2A, Z6.T1B.T2B.X1A.X2A, Z1.T1C.T2B.X1A.X2A, Z2.T1C.T2B.X1A.X2A, Z3.T1C.T2B.X1A.X2A, Z4.T1C.T2B.X1A.X2A, Z5.T1C.T2B.X1A.X2A, Z6.T1C.T2B.X1A.X2A, Z1.T1D.T2B.X1A.X2A, Z2.T1D.T2B.X1A.X2A, Z3.T1D.T2B.X1A.X2A, Z4.T1D.T2B.X1A.X2A, Z5.T1D.T2B.X1A.X2A, Z6.T1D.T2B.X1A.X2A, Z1.T1A.T2C.X1A.X2A, Z2.T1A.T2C.X1A.X2A, Z3.T1A.T2C.X1A.X2A, Z4.T1A.T2C.X1A.X2A, Z5.T1A.T2C.X1A.X2A, Z6.T1A.T2C.X1A.X2A, Z1.T1B.T2C.X1A.X2A, Z2.T1B.T2C.X1A.X2A, Z3.T1B.T2C.X1A.X2A, Z4.T1B.T2C.X1A.X2A, Z5.T1B.T2C.X1A.X2A, Z6.T1B.T2C.X1A.X2A, Z1.T1C.T2C.X1A.X2A, Z2.T1C.T2C.X1A.X2A, Z3.T1C.T2C.X1A.X2A, Z4.T1C.T2C.X1A.X2A, Z5.T1C.T2C.X1A.X2A, Z6.T1C.T2C.X1A.X2A, Z1.T1D.T2C.X1A.X2A, Z2.T1D.T2C.X1A.X2A, Z3.T1D.T2C.X1A.X2A, Z4.T1D.T2C.X1A.X2A, Z5.T1D.T2C.X1A.X2A, Z6.T1D.T2C.X1A.X2A, Z1.T1A.T2D.X1A.X2A, Z2.T1A.T2D.X1A.X2A, Z3.T1A.T2D.X1A.X2A, Z4.T1A.T2D.X1A.X2A, Z5.T1A.T2D.X1A.X2A, Z6.T1A.T2D.X1A.X2A, Z1.T1B.T2D.X1A.X2A, Z2.T1B.T2D.X1A.X2A, Z3.T1B.T2D.X1A.X2A, Z4.T1B.T2D.X1A.X2A, Z5.T1B.T2D.X1A.X2A, Z6.T1B.T2D.X1A.X2A, Z1.T1C.T2D.X1A.X2A, Z2.T1C.T2D.X1A.X2A, Z3.T1C.T2D.X1A.X2A, Z4.T1C.T2D.X1A.X2A, Z5.T1C.T2D.X1A.X2A, Z6.T1C.T2D.X1A.X2A, Z1.T1D.T2D.X1A.X2A, Z2.T1D.T2D.X1A.X2A, Z3.T1D.T2D.X1A.X2A, Z4.T1D.T2D.X1A.X2A, Z5T1 D.T2D.X1 A.X2A, Z6.T1D.T2D.X1A.X2A, Z1.T1A.T2A.X1B.X2A, Z2.T1A.T2A.X1B.X2A, Z3.T1A.T2A.X1B.X2A, Z4.T1A.T2A.X1B.X2A, Z5.T1A.T2A.X1B.X2A, Z6.T1A.T2A.X1B.X2A, Z1.T1B.T2A.X1B.X2A, Z2.T1B.T2A.X1B.X2A, Z3.T1B.T2A.X1B.X2A, Z4.T1B.T2A.X1B.X2A, Z5.T1B.T2A.X1B.X2A, Z6.T1B.T2A.X1B.X2A, Z1.T1C.T2A.X1B.X2A, Z2.T1C.T2A.X1B.X2A, Z3.T1C.T2A.X1B.X2A, Z4.T1C.T2A.X1B.X2A, Z5.T1C.T2A.X1B.X2A, Z6.T1C.T2A.X1B.X2A, Z1.T1D.T2A.X1B.X2A, Z2.T1D.T2A.X1B.X2A, Z3.T1D.T2A.X1B.X2A, Z4.T1D.T2A.X1B.X2A, Z5.T1D.T2A.X1B.X2A, Z6.T1D.T2A.X1B.X2A, Z1.T1A.T2B.X1B.X2A, Z2.T1A.T2B.X1B.X2A, Z3.T1A.T2B.X1B.X2A, Z4.T1A.T2B.X1B.X2A, Z5.T1A.T2B.X1B.X2A, Z6.T1A.T2B.X1B.X2A, Z1.T1B.T2B.X1B.X2A, Z2.T1B.T2B.X1B.X2A, Z3.T1B.T2B.X1B.X2A, Z4.T1B.T2B.X1B.X2A, Z5.T1B.T2B.X1B.X2A, Z6.T1B.T2B.X1B.X2A, Z1.T1C.T2B.X1B.X2A, Z2.T1C.T2B.X1B.X2A, Z3.T1C.T2B.X1B.X2A, Z4.T1C.T2B.X1B.X2A, Z5.T1C.T2B.X1B.X2A, Z6.T1C.T2B.X1B.X2A, Z1.T1D.T2B.X1B.X2A, Z2.T D.T2B.X1B.X2A, Z3.T1D.T2B.X1B.X2A, Z4.T1D.T2B.X1B.X2A, Z5.T1D.T2B.X1B.X2A, Z6.T1D.T2B.X1B.X2A, Z1.T1A.T2C.X1B.X2A, Z2.T1A.T2C.X1B.X2A, Z3.T1A.T2C.X1B.X2A, Z4.T1A.T2C.X1B.X2A, Z5.T1A.T2C.X1B.X2A, Z6.T1A.T2C.X1B.X2A, Z1.T1B.T2C.X1B.X2A, Z2.T1B.T2C.X1B.X2A, Z3.T1B.T2C.X1B.X2A, Z4.T1B.T2C.X1B.X2A, Z5.T1B.T2C.X1B.X2A, Z6.T1B.T2C.X1B.X2A, Z1.T1C.T2C.X1B.X2A, Z2.T1C.T2C.X1B.X2A, Z3.T1C.T2C.X1B.X2A, Z4.T1C.T2C.X1B.X2A, Z5.T1C.T2C.X1B.X2A, Z6.T1C.T2C.X1B.X2A, Z1.T1D.T2C.X1B.X2A, Z2.T1D.T2C.X1B.X2A, Z3.T1D.T2C.X1B.X2A, Z4.T1D.T2C.X1B.X2A, Z5.T1D.T2C.X1B.X2A, Z6.T1D.T2C.X1B.X2A, Z1.T1A.T2D.X1B.X2A, Z2.T1A.T2D.X1B.X2A, Z3.T1A.T2D.X1B.X2A, Z4.T1A.T2D.X1B.X2A, Z5.T1A.T2D.X1B.X2A, Z6.T1A.T2D.X1B.X2A, Z1.T1B.T2D.X1B.X2A, Z2.T1B.T2D.X1B.X2A, Z3.T1B.T2D.X1B.X2A, Z4.T1B.T2D.X1B.X2A, Z5.T1B.T2D.X1B.X2A, Z6.T1B.T2D.X1B.X2A, Z1.T1C.T2D.X1B.X2A, Z2.T1C.T2D.X1B.X2A, Z3.T1C.T2D.X1B.X2A, Z4.T1C.T2D.X1B.X2A, Z5.T1C.T2D.X1B.X2A, Z6.T1C.T2D.X1B.X2A, Z1.T1D.T2D.X1B.X2A, Z2.T1D.T2D.X1B.X2A, Z3.T1D.T2D.X1B.X2A, Z4.T1D.T2D.X1B.X2A, Z5.T1D.T2D.X1B.X2A, Z6.T1D.T2D.X1B.X2A, Z1.T1A.T2A.X1C.X2A, Z2.T1A.T2A.X1C.X2A, Z3.T1A.T2A.X1C.X2A, Z4.T1A.T2A.X1C.X2A, Z5.T1A.T2A.X1C.X2A, Z6.T4.A.T2A.X1 C.X2A, Z1.T B.T2A.X1CX2A, Z2.T1B.T2A.X1C.X2A, Z3.T1 B.T2A.X1CX2A, Z4.T1B.T2A.X1C.X2A, Z5.T1B.T2A.X1C.X2A, Z6.T1B.T2A.X1C.X2A, Z1.T1C.T2A.X1C.X2A, Z2.T1C.T2A.X1C.X2A, Z3.T1C.T2A.X1C.X2A, Z4.T1 CT2A.X1 C.X2A, Z5.T1C.T2A.X1C.X2A, Z6.T1C.T2A.X1C.X2A, Z1.T1D.T2A.X1C.X2A, Z2.T1D.T2A.X1C.X2A, Z3.T1D.T2A.X1C.X2A, Z4.T1D.T2A.X1C.X2A, Z5.T1D.T2A.X1C.X2A, Z6.T1D.T2A.X1C.X2A, Z1.T1A.T2B.X1C.X2A, Z2.T1A.T2B.X1C.X2A, Z3.T1A.T2B.X1C.X2A, Z4.T1A.T2B.X1C.X2A, Z5.T1A.T2B.X1CX2A, Z6.T A.T2B.X1C.X2A, Z1.T1B.T2B.X1C.X2A, Z2.T1B.T2B.X1C.X2A, 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Z3.T1A.T2A.X1D.X2E, Z4.T1A.T2A.X1D.X2E, Z5.T1A.T2A.X1D.X2E, Z6.T1A.T2A.X1D.X2E, Z1.T1B.T2A.X1D.X2E, Z2.T1B.T2A.X1D.X2E, Z3.T1B.T2A.X1D.X2E, Z4.T1B.T2A.X1D.X2E, Z5.T1B.T2A.X1D.X2E, Z6.T1B.T2A.X1D.X2E, Z1.T1C.T2A.X1D.X2E, Z2.T1C.T2A.X1D.X2E, Z3.T1C.T2A.X1D.X2E, Z4.T1C.T2A.X1D.X2E, Z5.T1C.T2A.X1D.X2E, Z6.T1C.T2A.X1D.X2E, Z1.T1D.T2A.X1D.X2E, Z2.T1D.T2A.X1D.X2E, Z3.T1D.T2A.X1D.X2E, Z4.T1D.T2A.X1D.X2E, Z5.T1D.T2A.X1D.X2E, Z6.T1D.T2A.X1D.X2E, Z1.T1A.T2B.X1D.X2E, Z2.T1A.T2B.X1D.X2E, Z3.T1A.T2B.X1D.X2E, Z4.T1A.T2B.X1D.X2E, Z5.T1A.T2B.X1D.X2E, Z6.T1A.T2B.X1D.X2E, Z1.T1B.T2B.X1D.X2E, Z2.T1B.T2B.X1D.X2E, Z3.T1B.T2B.X1D.X2E, Z4.T1B.T2B.X1D.X2E, Z5.T1B.T2B.X1D.X2E, Z6.T1B.T2B.X1D.X2E, Z1.T1C.T2B.X1D.X2E, Z2.T1C.T2B.X1D.X2E, Z3.T1C.T2B.X1D.X2E, Z4.T1C.T2B.X1D.X2E, Z5.T1C.T2B.X1D.X2E, Z6.T1C.T2B.X1D.X2E, Z1.T1D.T2B.X1D.X2E, Z2.T1D.T2B.X1D.X2E, Z3.T1D.T2B.X1D.X2E, Z4.T1D.T2B.X1D.X2E, Z5.T1D.T2B.X1D.X2E, Z6.T1D.T2B.X1D.X2E, Z1.T1 A.T2CX1 D.X2E, Z2.T1A.T2C.X1D.X2E, Z3.T1A.T2C.X1D.X2E, Z4.T1A.T2C.X1D.X2E, Z5.T1A.T2C.X1D.X2E, Z6.T1A.T2C.X1D.X2E, Z1.T1B.T2C.X1D.X2E, Z2.T1B.T2C.X1D.X2E, Z3.T1B.T2C.X1D.X2E, Z4.T1B.T2C.X1D.X2E, Z5.T1B.T2C.X1D.X2E, Z6.T1B.T2C.X1D.X2E, Z1.T1C.T2C.X1D.X2E, Z2.T1C.T2C.X1D.X2E, Z3.T1C.T2C.X1D.X2E, Z4.T1C.T2C.X1D.X2E, Z5.T1C.T2C.X1D.X2E, Z6.T1C.T2C.X1D.X2E, Z1.T1D.T2C.X1D.X2E, Z2.T1D.T2C.X1D.X2E, Z3.T1D.T2C.X1D.X2E, Z4.T1D.T2C.X1D.X2E, Z5.T1D.T2C.X1D.X2E, Z6.T1D.T2C.X1D.X2E, Z1.T1A.T2D.X1D.X2E, Z2.T1A.T2D.X1D.X2E, Z3.T1A.T2D.X1D.X2E, Z4.T1A.T2D.X1D.X2E, Z5.T1A.T2D.X1D.X2E, Z6.T1A.T2D.X1D.X2E, Z1.T1B.T2D.X1D.X2E, Z2.T1B.T2D.X D.X2E, Z3.T1B.T2D.X1D.X2E, Z4.T1B.T2D.X1D.X2E, Z5.T1B.T2D.X1D.X2E, Z6.T1B.T2D.X1D.X2E, Z1.T1C.T2D.X1D.X2E, Z2.T1C.T2D.X1D.X2E, Z3.T1C.T2D.X1D.X2E, Z4.T1C.T2D.X1D.X2E, Z5.T1C.T2D.X1D.X2E, Z6.T1C.T2D.X1D.X2E, Z1.T1D.T2D.X1D.X2E, Z2.T1D.T2D.X1D.X2E, Z3.T1D.T2D.X1D.X2E, Z4.T1D.T2D.X1D.X2E, Z5.T1D.T2D.X1D.X2E, Z6.T1D.T2D.X1D.X2E, Z1.T1A.T2A.X1E.X2E, Z2.T1A.T2A.X1E.X2E, Z3.T1A.T2A.X1E.X2E, Z4.T1A.T2A.X1E.X2E, Z5.T1A.T2A.X1E.X2E, Z6.T1A.T2A.X1E.X2E, Z1.T1B.T2A.X1E.X2E, Z2.T1B.T2A.X1E.X2E, Z3.T1B.T2A.X1E.X2E, Z4.T1B.T2A.X1E.X2E, Z5.T1B.T2A.X1E.X2E, Z6.T1B.T2A.X1E.X2E, Z1.T1C.T2A.X1E.X2E, Z2.T1C.T2A.X1E.X2E, Z3.T1C.T2A.X1E.X2E, Z4.T1C.T2A.X1E.X2E, Z5.T1C.T2A.X1E.X2E, Z6.T1C.T2A.X1E.X2E, Z1.T1D.T2A.X1E.X2E, Z2.T1D.T2A.X1E.X2E, Z3.T1D.T2A.X1E.X2E, Z4.T1D.T2A.X1E.X2E, Z5.T1D.T2A.X1E.X2E, Z6.T1D.T2A.X1E.X2E, Z1.T1A.T2B.X1E.X2E, Z2.T1A.T2B.X1E.X2E, Z3.T1A.T2B.X1E.X2E, Z4.T1A.T2B.X1E.X2E, Z5.T1A.T2B.X1E.X2E, Z6.T1A.T2B.X1E.X2E, Z1.T1B.T2B.X1E.X2E, Z2.T1B.T2B.X1E.X2E, Z3.T1B.T2B.X1E.X2E, Z4.T1B.T2B.X1E.X2E, Z5.T1B.T2B.X1E.X2E, Z6.T1B.T2B.X1E.X2E, Z1.T1C.T2B.X1E.X2E, Z2.T1C.T2B.X1E.X2E, Z3.T1C.T2B.X1E.X2E, Z4.T1C.T2B.X1E.X2E, Z5.T1C.T2B.X1E.X2E, Z6.T1C.T2B.X1E.X2E, Z1.T1D.T2B.X1E.X2E, Z2.T1D.T2B.X1E.X2E, Z3.T1D.T2B.X1E.X2E, Z4.T1D.T2B.X1E.X2E, Z5.T1D.T2B.X1E.X2E, Z6.T1D.T2B.X1E.X2E, Z1.T1 A.T2CX1 E.X2E, Z2.T1A.T2C.X1E.X2E, Z3.T1A.T2C.X1E.X2E, Z4.T1A.T2C.X1E.X2E, Z5.T1A.T2C.X1E.X2E, Z6.T1A.T2C.X1E.X2E, Z1.T1B.T2C.X1E.X2E, Z2.T1B.T2C.X1E.X2E, Z3.T1B.T2C.X1E.X2E, Z4.T1B.T2C.X1E.X2E, Z5.T1 B.T2CX1 E.X2E, Z6.T1B.T2C.X1E.X2E, Z1.T1C.T2C.X E.X2E, Z2.T1C.T2C.X1E.X2E, Z3.T1C.T2C.X1E.X2E, Z4.T1C.T2C.X1E.X2E, Z5.T1C.T2C.X1E.X2E, Z6.T1C.T2C.X1E.X2E, Z1.T1D.T2C.X1E.X2E, Z2.T1D.T2C.X1E.X2E, Z3.T1D.T2C.X1E.X2E, Z4.T1D.T2C.X1E.X2E, Z5.T1D.T2C.X1E.X2E, Z6.T1D.T2C.X1E.X2E, Z1.T1A.T2D.X1E.X2E, Z2.T1A.T2D.X1E.X2E, Z3.T1 A.T2D.X1 E.X2E, Z4.T1A.T2D.X1E.X2E, Z5.T1 A.T2D.X1 E.X2E, Z6.T1 A.T2D.X1E.X2E, Z1.T1B.T2D .X1E.X2E, Z2.T1B.T2D.X1E.X2E, Z3.T1B.T2D.X1E.X2E, Z4.T1B.T2D.X1E.X2E, Z5.T1B.T2D.X1E.X2E, Z6.T1B.T2D .X1E.X2E, Z1.T1C.T2D.X1E.X2E, Z2.T1 C.T2D.X1 E.X2E, Z3.T1C.T2D.X1E.X2E, Z4.T1C.T2D.X1E.X2E, Z5.T1C .T2D.X1 E.X2E, Z6.T1C.T2D.X1E.X2E, Z1.T1D.T2D.X1E.X2E, Z2.T1 D.T2D.X1 E.X2E, Z3.T1 D.T2D.X1 E. X2E, Z4.T1D.T2D.X1E.X2E, Z5.T1D.T2D.X1E.X2E, and Z6.T1D.T2D.X1E.X2E. In yet another embodiment, the compounds selected from Formula I are named below in a tabular format (Table 12), such as the compounds of General Formula III (the following): Formula III wherein 1, 2, 3, 4, and 5 are defined in Tables 7 to 11 below. Each compound is designated in a tabular form, by combining the "code" that represents each structural fraction, using the following syntax: 1.2.3.4.5. Therefore, for example, 1 a.2a.3a.4a.5a represents the following structure: Table 7: Structures "1" ??? ?? ??? ?? ?? ?? Table 9: Structures "3" Code Structure "3" 3a -0-CH2- (5-t-azole) 3b -0-CH3- (3-pyridyl) 3c -NH-CH2- (5-thiazolyl) 3d -NH-CH2- (3-pyridyl) 3e -N (CH3) -CH2- (5-thiazolyl) 3f -N (CH3) -CH2- (3-pyridyl) 3g -N (CH3) - (5-thiazolyl) 10 3h -N (CH3) - (3-pyridyl) Table 10: Structures "4" 25 Table 11: Structures "5" Code Structure "5" 5a n-propyl 5b -butyl-5C-CH2-cyclohexyl 5d -CH2-phenol 5e -CH2- (4-methoxy-phenol) 5f -CH2 - (3-fluoro-phenol) 5g -CH2- (4-pyridyl) 5h -CH2- (3-pyridyl) 5-CH2- (2-pyridyl) Code Structure "5" 5j -CH2CH2- (4-morpholinyl) 5k 51 5m 5n 5th Table 12: List of structures of compounds of Formula II a.2a.3a.4a.5a., 1 b.2a.3a.4a.5a., 1f.2a.3a.4a.5a., 1 .2a. 3a.4a.5a, j.2a.3a.4a.5a., 1 p.2a.3a.4a.5a., 1a.2b.3a.4a.5a., 1b.2b.3a.4a.5a. f.2b.3a.4a.5a., 1 h.2b.3a.4a.5a., 1j.2b.3a.4a.5a., 1 p.2b.3a.4a.5a. a.2e.3a.4a.5a., 1 b.2e.3a.4a.5a., 1f.2e.3a.4a.5a., 1 h.2e.3a.4a.5a. j.2e.3a.4a.5a., 1 p.2e.3a.4a.5a., 1a.2f.3a.4a.5a., 1b.2f.3a.4a.5a., f.2f.3a .4a.5a., 1h.2f.3a.4a.5a., 1j.2f.3a.4a.5a., 1p.2f.3a.4a.5a., A.2i.3a.4a.5a .. 1 b.2i.3a.4a.5a .. 1f.2i.3a.4a.5a., 1 h.2i.3a.4a.5a., j.2¡.3a.4a.5a., 1 p.2i.3a.4a.5a., 1 a.2m.3a.4a.5a 1 b.2m.3a.4a.5a. f.2m.3a.4a.5a., 1 h.2m.3a.4a.5a. 1 j.2m.3a.4a.5a. 1 p.2m.3a.4a.5a. a.2o.3a.4a.5a., 1 b.2o.3a.4a.5a. 1f.2o.3a.4a.5a., 1 h.2o.3a.4a.5a. j.2o.3a.4a.5a., 1 p.2o.3a.4a.5a. 1a.2u.3a.4a.5a. 1 b.2u.3a.4a.5a. f.2u.3a.4a.5a., 1 h.2u.3a.4a.5a. 1 j.2u.3a.4a.5a., 1 p.2u.3a.4a.5a. a.2y.3a.4a.5a., 1 b.2y.3a.4a.5a. 1f.2y.3a.4a.5a., 1h.2y.3a.4a.5a. j.2y.3a.4a.5a., 1 p.2y.3a.4a.5a. 1 a.2a.3b.4a.5a. 1b.2a.3b.4a.5a. f.2a.3b.4a.5a., 1 h.2a.3b.4a.5a. 1 j.2a.3b.4a.5a., 1p.2a.3b.4a.5a. a.2b.3b.4a.5a., 1b.2b.3b.4a.5a. 1f.2b.3b.4a.5a., 1h.2b.3b.4a.5a. j.2b.3b.4a.5a., 1p.2b.3b.4a.5a. 1 a.2e.3b.4a.5a. 1b.2e.3b.4a.5a. f.2e.3b.4a.5a., 1h.2e.3b.4a.5a. 1j.2e.3b.4a.5a., 1 p.2e.3b.4a.5a. a.2f.3b.4a.5a., 1b.2f.3b.4a.5a., 1f.2f.3b.4a.5a., 1h.2f.3b.4a.5a., j.2f.3b. 4a.5a., 1p.2f.3b.4a.5a., 1a.2i.3b.4a.5a., 1b.2i.3b.4a.5a., F.2i.3b.4a.5a., 1 h.2i.3b.4a.5a., 1 j.2¡.3b.4a.5a., 1 p.2¡.3b.4a.5a., a.2m.3b.4a.5a., 1 b .2m.3b.4a.5a 1f.2m.3b.4a.5a. 1 h.2m.3b.4a.5a j.2m.3b.4a.5a., 1 p.2m.3b.4a.5a 1 a.2o.3b.4a.5a 1b.2o.3b.4a.5a. f.2o.3b.4a.5a., 1h.2o.3b.4a.5a. 1 j.2o.3b.4a.5a. 1 p.2o.3b.4a.5a. a.2u.3b.4a.5a., 1b.2u.3b.4a.5a. 1f.2u.3b.4a.5a. 1h.2u.3b.4a.5a. j.2u.3b.4a.5a., 1 p.2u.3b.4a.5a. 1 a.2y.3b.4a.5a 1b.2y.3b.4a.5a. f.2y.3b.4a.5a., 1h.2y.3b.4a.5a. 1 j.2y.3b.4a.5a. 1 p.2y.3b.4a.5a. a.2a.3e.4a.5a., 1 b.2a.3e.4a.5a 1 f.2a.3e.4a.5a. 1 h.2a.3e.4a.5a j.2a.3e.4a.5a., 1p.2a.3e.4a.5a 1a.2b.3e.4a.5a 1b.2b.3e.4a.5a f. 2b.3e.4a.5a., 1h.2b.3e.4a.5a 1j.2b.3e.4a.5a. 1p.2b.3e.4a.5a a.2e.3e.4a.5a., 1 b.2e.3e.4a.5a 1f.2e.3e.4a.5a. 1 h.2e.3e.4a.5a j.2e.3e.4a.5a., 1p.2e.3e.4a.5a 1a.2f.3e.4a.5a. 1b.2f.3e.4a.5a. f.2f.3e.4a.5a., 1 h.2f.3e.4a.5a., 1 j.2f.3e.4a.5a., 1 p.2f.3e.4a.5a., a.2i .3e.4a.5a., 1 b.2i.3e.4a.5a., 1 f.2i.3e.4a.5a., 1h.2i.3e.4a.5a., J.2i.3e.4a .5a., 1 p.2i.3e.4a.5a., 1 a.2m.3e.4a.5a., 1 b.2m.3e.4a.5a. f.2m.3e.4a.5a., 1 h.2m.3e.4a.5a., 1 j.2m.3e.4a.5a., 1 p.2m.3e.4a.5a. a.2o.3e.4a.5a., 1 b.2o.3e.4a.5a., 1 f.2o.3e.4a.5a., 1 h.2o.3e.4a.5a. j.2o.3e.4a.5a., 1 p.2o.3e.4a.5a., 1 a.2u.3e.4a.5a., 1 b.2u.3e.4a.5a. f.2u.3e.4a.5a., 1 h.2u.3e.4a.5a., 1 j.2u.3e.4a.5a., 1 p.2u.3e.4a.5a. a.2y.3e.4a.5a., 1 b.2y.3e.4a.5a., 1 f.2y.3e.4a.5a., 1 h.2y.3e.4a.5a. j.2y.3e.4a.5a., 1 p.2y.3e.4a.5a., 1a.2a.3g.4a.5a., 1 b.2a.3g.4a.5a. f.2a.3g.4a.5a., 1 h.2a.3g.4a.5a., 1 j.2a.3g.4a.5a., 1 p.2a.3g.4a.5a. a.2b.3g.4a.5a., 1 b.2b.3g.4a.5a., 1f.2b.3g.4a.5a., 1 .2b.3g.4a.5a. j.2b.3g.4a.5a., 1 p.2b.3g.4a.5a., 1 a.2e.3g.4a.5a., 1 b.2e.3g.4a.5a. f.2e.3g.4a.5a., 1 h.2e.3g.4a.5a., 1j.2e.3g.4a.5a., 1 p.2e.3g.4a.5a. a.2f.3g.4a.5a., 1 b; 2f.3g.4a.5a., 1f.2f.3g.4a.5a., 1 h.2f.3g.4a.5a., j.2f. 3g.4a.5a., 1 p.2f.3g.4a.5a., 1a.2i.3g.4a.5a., 1 b.2i.3g.4a.5a., F.2L3g.4a.5a. , 1 h.2i.3g.4a.5a., 1 j.2i.3g.4a.5a., 1 p.2i.3g.4a.5a., A.2m.3g.4a.5a., 1 b .2m.3g.4a.5a., 1f.2m.3g.4a.5a., 1 h.2m.3g.4a.5a j.2m.3g.4a.5a., 1 p.2m.3g.4a .5a., 1 a.2o.3g.4a.5a., 1 b.2o.3g.4a.5a. f.2o.3g.4a.5a., 1 h.2o.3g: 4a.5a., 1j.2o.3g.4a.5a., 1 p.2o.3g.4a.5a. a.2u.3g.4a.5a., 1 b.2u.3g.4a.5a., 1f.2u.3g.4a.5a., 1 h.2u.3g.4a.5a. j.2u.3g.4a.5a., 1 p.2u.3g.4a.5a., 1a.2y.3g.4a.5a., 1 b.2y.3g.4a.5a. f.2y.3g.4a.5a., 1 h.2y.3g.4a.5a., 1 j.2y.3g.4a.5a., 1 p.2y .3g.4a.5a. a.2a.3a.4d.5a., 1 b.2a.3a.4d.5a., 1f.2a.3a.4d.5a., 1 h.2a.3a.4d.5a. j.2a.3a.4d.5a., 1 p.2a.3a.4d.5a., 1a.2b.3a.4d.5a., 1 b.2b.3a.4d.5a. f.2b.3a.4d.5a., 1 h.2b.3a.4d.5a., 1j.2b.3a.4d.5a., 1 p.2b.3a.4d.5a. a.2e.3a.4d.5a., 1 b.2e.3a.4d.5a., 1f.2e.3a.4d.5a., 1 h.2e.3a.4d.5a. j.2e.3a.4d.5a., 1 p.2e.3a.4d.5a., 1a.2f.3a.4d.5a., 1 b.2f.3a.4d.5a., f.2f. 3a.4d.5a., 1 h.2f.3a.4d.5a., 1j.2f.3a.4d.5a., 1p.2f.3a.4d.5a., A.2i.3a.4d.5a ., 1 b.2i.3a.4d.5a., 1f.2i.3a.4d.5a., 1h.2i.3a.4d.5a., J.2i.3a.4d.5a., 1 p. 2i.3a.4d.5a., 1a.2m.3a.4d.5a., 1 b.2m.3a.4d.5a f.2m.3a.4d.5a., 1 h.2m.3a.4d. 5a., 1 j.2m.3a.4d.5a., 1 p.2m.3a.4d.5a a.2o.3a.4d.5a., 1 b.2o.3a.4d.5a., 1f. 2o.3a.4d.5a., 1 h.2o.3a.4d.5a. j.2o.3a.4d.5a., 1 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1a.2o.3b.4a.5d., 1 b.2o.3b.4a.5d. f.2o.3b.4a.5d., 1h.2o.3b.4a.5d. 1j.2o.3b.4a.5d., 1 p.2o.3b.4a.5d. a.2u.3b.4a.5d., 1b.2u.3b.4a.5d 1f.2u.3b.4a.5d "1 h.2u.3b.4a.5d. j.2u.3b.4a.5d., 1 p.2u.3b.4a.5d. 1a.2y.3b.4a.5d., 1 b.2y.3b.4a.5d. f.2y.3b.4a.5d., 1h.2y.3b.4a.5d. 1j.2y.3b.4a.5d., 1 p.2y.3b.4a.5d. a.2a.3e.4a.5d., 1b.2a.3e.4a.5d 1f.2a.3e.4a.5d., 1 h.2a.3e.4a.5d j.2a.3e.4a.5d ., 1 p.2a.3e.4a.5d. 1a.2b.3e.4a.5d., 1 b.2b.3e.4a.5d. f.2b.3e.4a.5d., 1h.2b.3e.4a.5d. 1j.2b.3e.4a.5d., 1 p.2b.3e.4a.5d a.2e.3e.4a.5d., 1b.2e.3e.4a.5d 1f.2e.3e.4a.5d ., 1 h.2e.3e.4a.5d j.2e.3e.4a.5d., 1p.2e.3e.4a.5d. 1a.2f.3e.4a.5d., 1 b.2f .3e.4a.5d f.2f.3e.4a.5d., 1h.2f.3e.4a.5d. 1j.2f.3e.4a.5d., 1 p.2f.3e.4a.5d a.2i.3e.4a.5d., 1 b.2i.3e.4a.5d., 1f.2i.3e.4a.5d., 1h.2i.3e.4a.5d. j.2L3e.4a.5d., 1 p.2i.3e.4a.5d., 1 a.2m.3e.4a.5d., 1 b.2m.3e.4a.5d. f.2m.3e.4a.5d., 1 h.2m.3e.4a.5d., 1 j.2m.3e.4a.5d., 1 p.2m.3e.4a.5d. a.2o.3e.4a.5d., 1 b.2o.3e.4a.5d., 1f.2o.3e.4a.5d., 1 h.2o.3e.4a.5d. j.2o.3e.4a.5d., 1 p.2o.3e.4a.5d., 1a.2u.3e.4a.5d., 1 b.2u.3e.4a.5d. f.2u.3e.4a.5d., 1 h.2u.3e.4a.5d., 1 j.2u.3e.4a.5d., 1 p.2u.3e.4a.5d. a.2y.3e.4a.5d., 1 b.2y.3e.4a.5d., 1f.2y.3e.4a.5d., 1 h.2y.3e.4a.5d. j.2y.3e.4a.5d., 1 p.2y.3e.4a.5d., 1a.2a.3g.4a.5d., 1 b.2a.3g.4a.5d. f.2a.3g.4a.5d., 1 h.2a.3g.4a.5d., 1j.2a.3g.4a.5d., 1 p.2a.3g.4a.5d. a.2b.3g.4a.5d., 1 b.2b.3g.4a.5d., 1f.2b.3g.4a.5d., 1 h.2b.3g.4a.5d. j.2b.3g.4a.5d., 1 p.2b.3g.4a.5d., 1a.2e.3g.4a.5d., 1 b.2e.3g.4a.5d. f.2e.3g.4a.5d., 1 h.2e.3g.4a.5d., 1j.2e.3g.4a.5d., 1 p.2e.3g.4a.5d. a.2f.3g.4a.5d., 1 b.2f.3g.4a.5d., 1f.2f.3g.4a.5d., 1 h.2f.3g.4a.5d. j.2f.3g.4a.5d., 1 p.2f.3g.4a.5d., 1a.2i.3g.4a.5d., 1 b.2i.3g.4a.5d. f.2i.3g.4a.5d., 1 h.2i.3g.4a.5d., 1j.2i.3g.4a.5d., 1 p.2i.3g.4a.5d. a.2m.3g.4a.5d., 1 b.2m.3g.4a.5d., 1f.2m.3g.4a.5d., 1 h.2m.3g.4a.5d. j.2m.3g.4a.5d., 1 p.2m.3g.4a.5d., 1a.2o.3g.4a.5d., 1 b.2o.3g.4a.5d. f.2o.3g.4a.5d., 1 h.2o.3g.4a.5d., 1j.2o.3g.4a.5d. p.2o.3g.4a.5d., a.2u.3g.4a.5d., 1 b.2u.3g.4a.5d., 1f.2u.3g.4a.5d., 1 h.2u. 3g .4a.5d. j.2u.3g.4a.5d., 1 p.2u.3g.4a.5d., 1a.2y.3g.4a.5d., 1 b.2y.3g.4a.5d f.2y.3g. 4a.5d., 1 h.2y.3g.4a.5d., 1j.2y.3g.4a.5d., 1 p.2y.3g.4a.5d. a.2a.3a.4d.5d., 1 b.2a.3a.4d.5d., 1f.2a.3a.4d.5d., 1 h.2a.3a.4d.5d. j.2a.3a.4d.5d., 1 p.2a.3a.4d.5d., 1a.2b.3a.4d.5d., 1 b.2b.3a.4d.5d. f.2b.3a.4d.5d., 1 h.2b.3a.4d.5d., 1j.2b.3a.4d.5d., 1 p.2b.3a.4d.5d a.2e.3a.4d.5d, 1 b.2e.3a.4d.5d., 1 f.2e.3a.4d.5d. 1h.2e.3a.4d.5d. j.2e.3a.4d.5d., 1 p.2e.3a.4d.5d., 1 a.2f.3a.4d.5d 1b.2f.3a.4d.5d. f.2f.3a.4d.5d., 1 h.2f.3a.4d.5d., 1 j.2f.3a.4d.5d., 1p.2f.3a.4d.5d. a.2i.3a.4d.5d., 1 b.2L3a.4d.5d., 1 f.2i.3a.4d.5d., 1h.2i.3a.4d.5d. j.2i.3a.4d.5d., 1 p.2i.3a.4d.5d., 1 a.2m.3a.4d.5d. , 1b.2m.3a.4d.5d. f.2m.3a.4d.5d., 1 h.2m.3a.4d.5d., 1 j.2m.3a.4d.5d. 1p.2m.3a.4d.5d. a.2o.3a.4d.5d., 1 b.2o.3a.4d.5d., 1 f.2o.3a.4d.5d. 1h.2o.3a.4d.5d. j.2o.3a.4d.5d., 1 p.2o.3a.4d.5d "1 a.2u.3a.4d.5d. 1b.2u.3a.4d.5d. f.2u.3a.4d.5d., 1 h.2u.3a.4d.5d., 1 j.2u.3a.4d.5d. 1p.2u.3a.4d.5d. a.2y.3a.4d.5d., 1 b.2y.3a.4d.5d., 1 f .2y.3a.4d.5d. 1h.2y.3a.4d.5d. j.2y.3a.4d.5d., 1 p.2y.3a.4d.5d., 1 a.2a.3b.4d.5d. 1b.2a.3b.4d.5d. f.2a.3b.4d.5d., 1 h.2a.3b.4d.5d., 1 j.2a.3b.4d.5d. 1p.2a.3b.4d.5d. a.2b.3b.4d.5d., 1 b.2b.3b.4d.5d., 1 f.2b.3b.4d.5d. 1h.2b.3b.4d.5d. j.2b.3b.4d.5d., 1p.2b.3b.4d.5d., 1 a.2e.3b.4d.5d. 1b.2e.3b.4d.5d. f.2e.3b.4d.5d., 1 h.2e.3b.4d.5d., 1 j.2e.3b.4d.5d. 1p.2e.3b.4d.5d. a.2f.3b.4d.5d., 1 b.2f.3b.4d.5d., 1f.2f.3b.4d.5d. 1h.2f.3b.4d.5d. j.2f.3b.4d.5d., 1 p.2f.3b.4d.5d., 1 a.2i.3b.4d.5d. 1b.2i.3b.4d.5d. f.2i.3b.4d.5d., 1 h.2i.3b.4d.5d., 1 j.2i.3b.4d.5d. 1p.2i.3b.4d.5d. a.2m.3b.4d.5d., 1 b.2m.3b.4d.5d., 1 f .2m.3b.4d.5d 1 .2m.3b.4d.5d. j.2m.3b.4d.5d., 1 p.2m.3b.4d.5d., 1 a.2o.3b.4d.5d 1b.2o.3b.4d.5d. f.2o.3b.4d.5d., 1 h.2o.3b.4d.5d., 1 j.2o.3b.4d.5d. 1p.2o.3b.4d.5d. a.2u.3b.4d.5d., 1 b.2u.3b.4d.5d., 1 f .2u.3b.4d.5d 1h.2u.3b.4d.5d. j.2u.3b.4d.5d., 1p.2u.3b.4d.5d., 1 a.2y.3b.4d.5d 1b.-2y.3b.4d.5d. f.2y.3b.4d.5d., 1 h.2y.3b.4d.5d., 1 j.2y.3b.4d.5d. 1p.2y.3b.4d.5d. a.2a.3e.4d.5d., 1 b.2a.3e.4d.5d 1 f .2a.3e.4d.5d 1h.2a.3e.4d.5d 1j.2a.3e.4d.5d., 1 p.2a.3e.4d.5d., 1 a.2b.3e.4d.5d., 1 b.2b.3e.4d.5d. 1f.2b, 3e.4d.5d., 1 h.2b.3e.4d.5d., 1 j.2b.3e.4d.5d., 1 p.2b.3e.4d.5d. 1a.2e.3e.4d.5d., 1 b.2e.3e.4d.5d., 1f.2e.3e.4d.5d., 1 h.2e.3e.4d.5d. 1j.2e.3e.4d.5d., 1 p.2e.3e.4d.5d., 1a.2f.3e.4d.5d., 1 b.2f .3e.4d.5d. 1f.2f.3e.4d.5d., 1h.2f.3e.4d.5d., 1 j.2f.3e.4d.5d., 1 p.2f.3e.4d.5d. 1a.2i.3e.4d.5d., 1 b.2i.3e.4d.5d., 1 f.2i.3e.4d.5d., 1 h.2i .3e.4d.5d. 1j.2i.3e.4d.5d., 1 p.2i.3e.4d.5d., 1 a.2m.3e.4d.5d., 1 b.2m.3e.4d.5d. 1f.2m.3e.4d.5d., 1 h.2m.3e.4d.5d., 1 j.2m.3e.4d.5d., 1p.2m.3e.4d.5d. 1a.2o.3e.4d.5d., 1 b.2o.3e.4d.5d., 1 f.2o.3e.4d.5d., 1 h.2o.3e.4d.5d., 1j.2o .3e.4d.5d., 1p.2o.3e.4d.5d., 1 a.2u.3e.4d.5d., 1 b.2u.3e.4d.5d. 1f.2u.3e.4d.5d., 1 h.2u.3e.4d.5d., 1 j.2u.3e.4d.5d., 1 p.2u.3e.4d.5d. 1a.2y.3e.4d.5d., 1 b.2y.3e.4d.5d., 1f.2y.3e.4d.5d., 1 h.2y.3e.4d.5d. 1j.2y.3e.4d.5d., 1 p.2y.3e.4d.5d., 1 a.2a.3g.4d.5d., 1 b.2a.3g.4d.5d. 1f.2a.3g.4d.5d., 1 h.2a.3g.4d.5d., 1 j.2a.3g.4d.5d. , 1 p.2a.3g .4d.5d. 1a.2b.3g.4d.5d., 1 b.2b.3g.4d.5d., 1 f .2b.3g.4d.5d. , 1 h.2b.3g.4d.5d. 1j.2b.3g.4d.5d., 1 p.2b.3g.4d.5d., 1 a.2e.3g.4d.5d., 1 b.2e.3g.4d.5d. 1f.2e.3g.4d.5d., 1 h.2e.3g.4d.5d., 1 j.2e.3g.4d.5d., 1 p.2e.3g .4d.5d. 1a.2f.3g.4d.5d., 1 b.2f.3g.4d.5d., 1f.2f.3g.4d.5d., 1 h.2f.3g.4d.5d. 1j.2f3g.4d.5d., 1 p.2f .3g.4d.5d., 1 a.2i.3g.4d.5d., 1 b.2i.3g.4d.5d 1f.2i.3g.4d .5d., 1 h.2i.3g.4d.5d., 1 j.2i.3g.4d.5d., 1 p.2i.3g.4d.5d. 1a.2m.3g.4d.5d., 1 b.2m.3g.4d.5d., 1 f .2m.3g.4d.5d. , 1 h.2m.3g.4d.5d. 1j.2m.3g.4d.5d., 1 p.2m.3g.4d.5d., 1 a.2o.3g.4d.5d., 1 b.2o.3g.4d.5d. 1f.2o.3g.4d.5d., 1 h.2o.3g.4d.5d., 1 j.2o.3g.4d.5d. , 1 p.2o.3g.4d.5d. 1a.2u.3g.4d.5d., 1 b.2u.3g.4d.5d., 1 f .2u.3g.4d.5d. , 1 h.2u.3g.4d.5d. 1j.2u.3g.4d.5d., 1p.2u.3g.4d.5d., 1 a.2y.3g.4d.5d. , 1 b.2y.3g.4d.5d f.2y.3g.4d.5d., 1h.2y.3g.4d.5d., 1j.2y.3g.4d.5d., 1p.2y.3g.4d.5d. a.2a.3a.4f.5d., 1b.2a.3a.4f.5d., 1f.2a.3a.4f.5d. 1h.2a.3a.4f.5d. j.2a.3a.4f.5d., 1p.2a.3a.4f.5d., 1a.2b.3a.4f.5d. 1b.2b.3a.4f.5d. f.2b.3a.4f.5d., 1h.2b.3a.4f.5d., 1j.2b.3a.4f.5d., 1p.2b.3a.4f.5d. a.2e.3a.4f.5d., 1b.2e.3a.4f.5d., 1f.2e.3a.4f.5d. 1h.2e.3a.4f.5d. j.2e.3a.4f.5d., 1p.2e.3a.4f.5d., 1a.2f.3a.4f.5d. 1b.2f.3a.4f.5d. f.2f.3a.4f.5d., 1h.2f.3a.4f.5d., 1j.2f.3a.4f.5d., 1p.2f.3a.4f.5d. a.2i.3a.4f.5d., 1b.2i.3a.4f.5d., 1f.2i.3a.4f.5d., 1h.2i.3a.4f.5d. j.2i.3a.4f.5d., 1p.2i.3a.4f.5d., 1a.2m.3a.4f.5d., 1b.2m.3a.4f.5d. f.2m.3a.4f.5d., 1h.2m.3a.4f.5d., 1j.2m.3a.4f.5d. 1p.2m.3a.4f.5d. a.2o.3a.4f.5d., 1b.2o.3a.4f.5d., 1f.2o.3a.4f.5d. 1h.2o.3a.4f.5d. j.2o.3a.4f.5d., 1p.2o.3a.4f.5d., 1a.2u.3a.4f.5d. 1b.2u.3a.4f.5d. f.2u.3a.4f.5d., 1h.2u.3a.4f.5d., 1j.2u.3a.4f.5d. 1p.2u.3a.4f.5d. a.2y.3a.4f.5d., 1b.2y.3a.4f.5d., 1f.2y.3a.4f.5d. 1h.2y.3a.4f.5d j.2y.3a.4f.5d., 1p.2y.3a.4f.5d., 1a.2a.3b.4f.5d. 1b.2a.3b.4f.5d. f.2a.3b.4f.5d., 1h.2a.3b.4f.5d., 1j.2a.3b.4f.5d. 1p.2a.3b.4f.5d. a.2b.3b.4f.5d., 1b.2b.3b.4f.5d., 1f.2b.3b.4f.5d. 1h.2b.3b.4f.5d. j.2b.3b.4f.5d., 1p.2b.3b.4f.5d., 1a.2e.3b.4f.5d. 1b.2e.3b.4f.5d. f.2e.3b.4f.5d., 1h.2e.3b.4f.5d., 1j.2e.3b.4f.5d. 1p.2e.3b.4f.5d. a.2f.3b.4f.5d., 1b.2f.3b.4f.5d., 1f.2f.3b.4f.5d. 1h.2f.3b.4f.5d. j.2f.3b.4f.5d., 1p.2f.3b.4f.5d., 1a.2i.3b.4f.5d. 1b.2i.3b.4f.5d. f.2i.3b.4f.5d., 1h.2i.3b.4f.5d., 1j.2i.3b.4f.5d. 1p.2i.3b.4f.5d. a.2m.3b.4f.5d., 1b.2m.3b.4f.5d. 1f.2m.3b.4f.5d 1h.2m.3b.4f.5d. j.2m.3b.4f.5d., 1p.2m.3b.4f.5d., 1a.2o.3b.4f.5d 1b.2o.3b.4f.5d. f.2o.3b.4f.5d., 1h.2o.3b.4f.5d., 1j.2o.3b.4f.5d. 1p.2o.3b.4f.5d. 1a.2u.3b.4f.5d., 1b.2u.3b.4f.5d., 1f.2u.3b.4f.5d., 1h.2u.3b.4f.5d. 1j.2u.3b.4f.5d., 1p.2u.3b.4f.5d., 1a.2y.3b.4f.5d., 1b.2y.3b.4f.5d. 1f.2y.3b.4f.5d., 1h.2y.3b.4f.5d., 1j.2y.3b.4f.5d., 1p.2y.3b.4f.5d. 1a.2a.3e.4f.5d., 1b.2a.3e.4f.5d., 1f.2a.3e.4f.5d., 1h.2a.3e.4f.5d. 1j.2a.3e.4f.5d., 1 p.2a.3e.4f.5d., 1a.2b.3e.4f.5d., 1b.2b.3e.4f.5d. 1f.2b.3e.4f.5d., 1h.2b.3e.4f.5d., 1j.2b.3e.4f.5d., 1p.2b.3e.4f.5d 1a.2e.3e.4f.5d., 1b.2e.3e.4f.5d., 1f.2e.3e.4f.5d., 1h.2e.3e.4f.5d. 1j.2e.3e.4f.5d., 1p.2e.3e.4f.5d., 1a.2f.3e.4f.5d., 1b.2f.3e.4f.5d. 1f.2f.3e.4f.5d., 1h.2f.3e.4f.5d., 1j.2f.3e.4f.5d., - 1p.2f.3e.4f.5d. 1a.2i.3e.4f.5d., 1b.2i.3e.4f.5d., 1f.2i.3e.4f.5d., 1h.2i.3e.4f.5d. 1j.2i.3e.4f.5d., 1p.2i.3e.4f.5d., 1a.2m.3e.4f.5d., 1b.2m.3e.4f.5d. 1f.2m.3e.4f.5d., 1h.2m.3e.4f.5d., 1j.2m.3e.4f.5d., 1p.2m.3e.4f.5d. 1a.2o.3e.4f.5d., 1b.2o.3e.4f.5d., 1f.2o.3e.4f.5d., 1h.2o.3e.4f.5d. 1j.2o.3e.4f.5d., 1 p.2o.3e.4f.5d., 1a.2u.3e.4f.5d., 1b.2u.3e.4f.5d. 1f.2u.3e.4f.5d., 1h.2u.3e.4f.5d., 1j.2u.3e.4f.5d., 1p.2u.3e.4f.5d. 1a.2y.3e.4f.5d., 1b.2y.3e.4f.5d., 1f.2y.3e.4f.5d., 1h.2y.3e.4f.5d. 1j.2y.3e.4f.5d .. 1p.2y.3e.4f.5d., 1a.2a.3g.4f.5d., 1b.2a.3g.4f.5d. 1f.2a.3g.4f.5d., 1h.2a.3g.4f.5d., 1j.2a.3g.4f.5d., 1p.2a.3g.4f.5d 1a.2b.3g.4f.5d., 1b.2b.3g.4f.5d., 1f.2b.3g.4f.5d., 1h.2b.3g.4f.5d 1j.2b.3g.4f.5d., 1p.2b.3g.4f.5d., 1a.2e.3g.4f.5d., 1b.2e.3g.4f.5d 1f.2e.3g.4f.5d., 1h.2e.3g.4f.5d., 1j.2e.3g.4f.5d., 1p.2e.3g.4f.5d 1a.2f.3g.4f.5d., 1b.2f.3g.4f.5d., 1f.2f.3g.4f.5d., 1h.2f.3g.4f.5d 1j.2f.3g.4f.5d., 1p.2f.3g.4f.5d., 1a.2i.3g.4f.5d., 1b.2i.3g.4f.5d 1f.2i.3g.4f.5d., 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1j.2m.3a.4g.5d. 1 p.2m.3a.4g.5d. a.2o.3a.4g.5d 1b.2o.3a.4g.5d., 1f.2o.3a.4g.5d. 1h.2o.3a.4g.5d. j.2o.3a.4g.5d 1p.2o.3a.4g.5d., 1a.2u.3a.4g.5d. 1b.2u.3a.4g.5d. f.2u.3a.4g.5d. 1h.2u.3a.4g.5d., 1j.2u.3a.4g.5d. 1p.2u.3a.4g.5d. a.2y.3a.4g.5d 1b.2y.3a.4g.5d., 1f.2y.3a.4g.5d. 1h.2y.3a.4g.5d. j.2y.3a.4g.5d. 1p.2y.3a.4g.5d., 1a.2a.3b.4g.5d. 1b.2a.3b.4g.5d. f.2a.3b.4g.5d. 1h.2a.3b.4g.5d., 1j.2a.3b.4g.5d. 1p.2a.3b.4g.5d. a.2b.3b.4g.5d 1b: 2b.3b.4g.5d., 1f.2b.3b.4g.5d 1h.2b.3b.4g.5d. j.2b.3b.4g.5d 1p.2b.3b.4g.5d., 1a.2e.3b.4g.5d 1b.2e.3b.4g.5d. f.2e.3b.4g.5d. 1h.2e.3b.4g.5d., 1j.2e.3b.4g.5d. 1p.2e.3b.4g.5d. a.2f.3b.4g.5d 1b.2f.3b.4g.5d., 1f.2f.3b.4g.5d. 1h.2f.3b.4g.5d. j.2f.3b.4g.5d., 1p.2f.3b.4g.5d., 1a.2i.3b.4g.5d 1b.2i.3b.4g.5d. f.2i.3b.4g.5d., 1h.2i.3b.4g.5d., 1j.2i.3b.4g.5d., 1p.2i.3b.4g.5d. a.2m.3b.4g.5d 1b.2m.3b.4g.5d., 1f.2m.3b.4g.5d. 1h.2m.3b.4g.5d. j.2m.3b.4g.5d 1 p.2m.3b.4g.5d., 1a.2o.3b.4g.5d. 1b.2o.3b.4g.5d. f.2o.3b.4g.5d., 1h.2o.3b.4g.5d., 1j.2o.3b.4g.5d. 1p.2o.3b.4g.5d. a.2u.3b.4g.5d. 1b.2u.3b.4g.5d., 1f.2u.3b.4g.5d. 1h.2u.3b.4g.5d. j.2u.3b.4g.5d., 1 p.2u.3b.4g.5d., 1a.2y.3b.4g.5d. 1b.2y.3b.4g.5d. f.2y.3b.4g.5d., 1h.2y.3b.4g.5d., 1j.2y.3b.4g.5d. 1p.2y.3b.4g.5d. a.2a.3e.4g.5d. 1b.2a.3e.4g.5d., 1f.2a.3e.4g.5d. 1h.2a.3e.4g.5d. j.2a.3e.4g.5d., 1p.2a.3e.4g.5d., 1a.2b.3e.4g.5d. 1b.2b.3e.4g.5d. f.2b.3e.4g.5d., 1h.2b.3e.4g.5d., 1j.2b.3e.4g.5d. 1p.2b.3e.4g.5d. a.2e.3e.4g.5d. 1b.2e.3e.4g.5d., 1f.2e.3e.4g.5d. 1h.2e.3e.4g.5d. j.2e.3e.4g.5d., 1 p.2e.3e.4g.5d., 1a.2f.3e.4g.5d. 1b.2f.3e.4g.5d. f.2f.3e.4g.5d., 1h.2f.3e.4g.5d., 1j.2f.3e.4g.5d. 1p.2f.3e.4g.5d. a.2i.3e.4g.5d. 1b.2i.3e.4g.5d., 1f.2i.3e.4g.5d. 1h.2i.3e.4g.5d. j.2i.3e.4g.5d., 1 p.2i.3e.4g.5d., a.2m.3e.4g.5d., 1 b.2m.3e.4g.5d. f.2m.3e.4g.5d 1 h.2m.3e.4g.5d., 1j.2m.3e.4g.5d. 1p.2m.3e.4g.5d. a.2o.3e.4g.5d 1b.2o.3e.4g.5d., 1f.2o.3e.4g.5d. 1h.2o.3e.4g.5d. j.2o.3e.4g.5d 1 p.2o.3e.4g.5d., 1a.2u.3e.4g.5d. 1b.2u.3e.4g.5d. f.2u.3e.4g.5d. 1 h.2u.3e.4g.5d., 1 j.2u.3e.4g.5d. 1p.2u.3e.4g.5d. a.2y.3e.4g.5d 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1h.2a.3a.4h.5d. j.2a.3a.4h.5d., 1p.2a.3a.4h.5d., 1a.2b.3a.4h.5d. 1b.2b.3a.4h.5d. f.2b.3a.4h.5d. 1h.2b.3a.4h.5d., 1j.2b.3a.4h.5d. 1p.2b.3a.4h.5d. a.2e.3a.4h.5d 1b.2e.3a.4h.5d., 1f.2e.3a.4h.5d. 1h.2e.3a.4h.5d. j.2e.3a.4h.5d. 1p.2e.3a.4h.5d., 1a.2f.3a.4h.5d. 1b.2f.3a.4h.5d. f.2f.3a.4h.5d., 1h.2f.3a.4h.5d., 1j.2f.3a.4h.5d. 1p.2f.3a.4h.5d. a.2i.3a.4h.5d. 1b.2i.3a.4h.5d., 1f.2i.3a.4h.5d. 1h.2i.3a.4h.5d. j.2i.3a.4h.5d., 1p.2i.3a.4h.5d., a.2m.3a.4h.5d. 1b.2m.3a.4h.5d. f.2m.3a.4h.5d 1h.2m.3a.4h.5d., 1j.2m.3a.4h.5d 1 p.2m.3a.4h.5d. a.2o.3a.4h.5d 1b.2o.3a.4h.5d., 1f.2o.3a.4h.5d 1h.2o.3a.4h.5d. j.2o.3a.4h.5d 1p.2o.3a.4h.5d., 1a.2u.3a.4h.5d 1b.2u.3a.4h.5d. f.2u.3a.4h.5d. 1h.2u.3a.4h.5d., 1j.2u.3a.4h.5d 1p.2u.3a.4h.5d. a.2y.3a.4h.5d 1b.2y: 3a.4h.5d., 1f.2y.3a.4h.5d 1h.2y.3a.4h.5d. j.2y.3a.4h.5d. 1p.2y.3a.4h.5d., 1a.2a.3b.4h.5d 1b.2a.3b.4h.5d. f.2a.3b.4h.5d. 1h.2a.3b.4h.5d., 1j.2a.3b.4h.5d 1p.2a.3b.4h.5d. a.2b.3b.4h.5d 1b.2b.3b.4h.5d., 1f.2b.3b.4h.5d 1h.2b.3b.4h.5d. j.2b.3b.4h.5d., 1p.2b.3b.4h.5d., 1a.2e.3b.4h.5d., 1 b.2e.3b.4h.5d. f.2e.3b.4h.5d., 1 h.2e.3b.4h.5d., 1 j.2e.3b.4h.5d. , 1 p.2e.3b.4h.5d. a.2f.3b.4h.5d., 1 b.2f.3b.4h.5d., 1 f.2f .3b.4h.5d., 1 h.2f .3b.4h.5d. j.2f.3b.4h.5d., 1p.2f.3b.4h.5d., 1 a.2i.3b.4h.5d., 1 b.2i.3b.4h.5d. f.2i.3b.4h.5d., 1 h.2i.3b.4h.5d., 1 j.2i.3b.4h.5d., 1 p.2i.3b.4h.5d. a.2m.3b.4h.5d., 1 b.2m.3b.4h.5d., 1f.2m.3b.4h.5d., 1 h.2m.3b.4h.5d. j.2m.3b.4h.5d., 1 p.2m.3b.4h.5d., 1 a.2o.3b.4h.5d., 1 b.2o.3b.4h.5d. f.2o.3b.4h.5d., 1 h.2o.3b.4h.5d., 1 j.2o.3b.4h.5d., 1 p.2o.3b.4h.5d. a.2u.3b.4h.5d., 1 b.2u.3b.4h.5d., 1f.2u.3b.4h.5d., 1 h.2u.3b.4h.5d. j.2u.3b.4h.5d., 1p.2u.3b.4h.5d., 1 a.2y.3b.4h.5d., 1 b.2y.3b.4h.5d. f.2y.3b.4h.5d., 1 h.2y.3b.4h.5d., 1 j.2y.3b.4h.5d., 1 p.2y .3b.4h.5d. a.2a.3e.4h.5d., 1 b.2a.3e.4h .5d., 1f.2a.3e.4h.5d., 1 h.2a.3e.4h.5d. j.2a.3e.4h.5d., 1 p.2a.3e.4h.5d., 1 a.2b.3e.4h.5d., 1 b.2b.3e.4h.5d. f.2b.3e.4h.5d., 1 h.2b.3e.4h.5d., 1 j.2b.3e.4h.5d. , 1 p.2b.3e.4h.5d. a.2e.3e.4h.5d., 1 b.2e.3e.4h .5d., 1f.2e.3e.4h.5d., 1 h.2e.3e.4h.5d. j.2e.3e.4h.5d., 1 p.2e.3e.4h.5d., 1a.2f.3e.4h.5d., 1 b.2f .3e.4h.5d. f.2f.3e.4h.5d., 1 h.2f.3e.4h.5d., 1 j.2f.3e.4h.5d., 1 p.2f .3e.4h.5d. a.2i.3e.4h.5d., 1 b.2i.3e.4h.5d., 1f.2i.3e.4h.5d., 1 h.2i.3e.4h.5d. j.2i.3e.4h.5d., 1 p.2i.3e.4h.5d., 1 a.2m.3e.4h.5d., 1 b.2m.3e.4h.5d. f.2m.3e.4h.5d., 1 h.2m.3e.4h.5d., 1 j.2m.3e.4h.5d., 1 p.2m .3e.4h.5d. a.2o.3e.4h.5d., 1 b.2o.3e.4h.5d., 1 f.2o.3e.4h.5d., 1 h.2o.3e.4h.5d j.2o.3e .4h.5d., 1 p.2o.3e.4h.5d., 1 a.2u.3e.4h.5d., 1 b.2u.3e.4h.5d f.2u.3e.4h.5d. , 1 h.2u.3e.4h.5d., 1 a.2i.3e.4a.5f., 1b.2i.3e.4a.5f f.2i.3e.4a.5f., 1 h.2i. 3e.4a.5f., 1 j.2i.3e.4a.5f., 1 p.2i.3e.4a.5f a.2m.3e.4a.5f., 1 b.2m.3e.4a.5f ., 1 f .2m.3e.4a.5f. , 1 h.2m.3e.4a.5f 1 j.2m.3e.4a.5f., 1 p.2m.3e.4a.5f., 1a.2o.3e.4a.5f., 1b.2o.3e.4a.5f. 1f.2o.3e.4a.5f., 1h.2o.3e.4a.5f., 1j.2o.3e.4a.5f., 1p.2o.3e.4a.5f. 1 a.2u.3e.4a.5f., 1b.2u.3e.4a.5f., 1f.2u.3e.4a.5f., 1h.2u.3e.4a.5f. 1j.2u.3e.4a.5f., 1 p.2u.3e.4a.5f., 1 a.2y.3e.4a.5f., 1b.2y.3e.4a.5f. 1f.2y.3e.4a.5f., 1 h.2y.3e.4a.5f., 1j.2y.3e.4a.5f., 1p.2y.3e.4a.5f. 1a.2a.3g.4a.5f., 1b.2a.3g.4a.5f, 1f.2a.3g.4a.5f., 1h.2a.3g.4a.5f. 1j.2a.3g.4a.5f., 1 p.2a.3g.4a.5f., 1a.2b.3g.4a.5f., 1b.2b.3g.4a.5f. 1f.2b.3g.4a.5f., 1h.2b.3g.4a.5f, 1j.2b.3g.4a.5f., 1p.2b.3g.4a.5f. 1 a.2e.3g.4a.5f., 1b.2e.3g.4a.5f., 1f.2e.3g.4a.5f., 1h.2e.3g.4a.5f. 1j.2e.3g.4a.5f., 1 p.2e.3g.4a.5f., 1a.2f.3g.4a.5f., 1b.2f.3g.4a.5f. 1f.2f.3g.4a.5f., 1h.2f.3g.4a.5f., 1j.2f.3g.4a.5f, 1p.2f.3g.4a.5f. 1a.2i.3g.4a.5f., 1b.2i.3g.4a.5f., 1f.2i.3g.4a.5f., 1h.2i.3g.4a.5f. 1j.2i.3g.4a.5f., 1 p.2i.3g.4a.5f., 1a.2m.3g.4a.5f., 1b.2m.3g.4a.5f. 1f.2m.3g.4a.5f., 1h.2m.3g.4a.5f., 1j.2m.3g.4a.5f., 1 p.2m.3g.4a.5f. 1a.2o.3g.4a.5f., 1b.2o.3g.4a.5f., 1f.2o.3g.4a.5f., 1h.2o.3g.4a.5f. 1 j.2o.3g.4a.5f :, 1 p.2o.3g.4a.5f., 1 a.2u.3g.4a.5f., 1b.2u.3g.4a.5f. 1f.2u.3g.4a.5f., 1h.2u.3g.4a.5f., 1j.2u.3g.4a.5f., 1p.2u.3g.4a.5f. 1a.2y.3g.4a.5f., 1b.2y.3g.4a.5f., 1f.2y.3g.4a.5f., 1h.2y.3g.4a.5f. 1j.2y.3g.4a.5f., 1 p.2y.3g.4a.5f., 1a.2a.3a.4d.5f., 1b.2a.3a.4d.5f. 1f.2a.3a: 4d.5f., 1h.2a.3a.4d.5f., 1j.2a.3a.4d.5f., 1p.2a.3a.4d.5f. 1a.2b.3a.4d.5f., 1b.2b.3a.4d.5f., 1f.2b.3a.4d.5f., 1h.2b.3a.4d.5f. 1j.2b.3a.4d.5f., 1p.2b.3a.4d.5f., 1a.2e.3a.4d.5f., 1b.2e.3a.4d.5f. 1f.2e.3a.4d.5f., 1 h.2e.3a.4d.5f., 1j.2e.3a.4d.5f., 1p.2e.3a.4d.5f. 1a.2f.3a.4d.5f., 1b.2f.3a.4d.5f., 1f.2f.3a.4d.5f., 1h.2f.3a.4d.5f. 1j.2f.3a.4d.5f., 1p.2f.3a.4d.5f., 1a.2i.3a.4d.5f., 1b.2i.3a.4d.5f. 1f.2i.3a.4d.5f., 1h.2i.3a.4d.5f., 1j.2i.3a.4d.5f., 1p.2i.3a.4d.5f., 1 a.2m.3a.4d.5f., 1b.2m.3a.4d.5f., 1f.2m.3a.4d.5f., 1h.2m.3a.4d.5f., 1j.2m.3a.4d.5f., 1p.2m.3a.4d.5f, 1a.2o.3a.4d.5f., 1b.2o.3a.4d.5f., 1f.2o.3a.4d.5f., 1h.2o.3a.4d.5f., 1j.2o.3a.4d.5f., 1p.2o.3a.4d.5f., 1a.2u.3a.4d.5f., 1b.2u.3a.4d.5f., 1f.2u.3a.4d.5f., 1h.2u.3a.4d.5f., 1j.2u.3a.4d.5f., 1p.2u.3a.4d.5f., 1a.2y.3a.4d.5f., 1b.2y.3a.4d.5f., 1f.2y.3a.4d.5f., 1h.2y.3a.4d.5f., 1j.2y.3a.4d.5f., 1p.2y.3a.4d.5f., 1a.2a.3b.4d.5f., 1b.2a.3b.4d.5f., 1f.2a.3b.4d.5f., 1h.2a.3b.4d.5f., 1j.2a.3b.4d.5f., 1p.2a.3b.4d.5f., 1a.2b.3b.4d.5f., 1b.2b.3b.4d.5f., 1f.2b.3b.4d.5f., 1h.2b.3b.4d.5f., 1j.2b.3b.4d.5f., 1p.2b.3b.4d.5f., 1a.2e.3b.4d.5f., 1b.2e.3b.4d.5f.,, 1f.2e.3b.4d.5f, 1h.2e.3b.4d.5f, 1j.2e.3b.4d.5f., 1p.2e.3b.4d.5f., 1a.2f.3b.4d.5f., 1b.2f.3b.4d.5f., 1f.2f.3b.4d.5f., 1h.2f.3b.4d.5f., 1j.2f.3b.4d.5f., 1p.2f.3b.4d.5f., 1a.2i.3b.4d.5f., 1b.2i.3b.4d.5f., 1f.2i.3b.4d.5f., 1h.2i.3b.4d.5f., 1j.2i.3b.4d.5f., 1p.2i.3b.4d.5f., 1a.2m.3b.4d.5f., 1b.2m.3b.4d.5f., 1f.2m.3b.4d.5f., 1h.2m.3b.4d.5f.,, 1j.2m.3b.4d.5f, 1p.2m.3b.4d.5f., 1a.2o.3b.4d.5f., 1b.2o.3b.4d.5f., 1f.2o.3b.4d.5f., 1h.2o.3b.4d.5f., 1j.2o.3b.4d.5f., 1p.2o.3b.4d.5f., 1a.2u.3b.4d.5f., 1b.2u.3b.4d.5f., 1f.2u.3b.4d.5f., 1h.2u.3b.4d.5f., 1j.2u.3b.4d.5f., 1p.2u.3b.4d.5f., 1a.2y.3b.4d.5f., 1b.2y.3b.4d.5f.,, 1f.2y.3b.4d.5f, 1h.2y.3b.4d.5f., 1j.2y.3b.4d.5f., 1p.2y.3b.4d.5f., 1a.2a.3e.4d.5f., 1b.2a.3e.4d.5f., 1f.2a.3e.4d.5f., 1h.2a.3e.4d.5f., 1j.2a.3e.4d.5f., 1p.2a.3e.4d.5f., 1a.2b.3e.4d.5f., 1b.2b.3e.4d.5f., 1f.2b.3e.4d.5f., 1h.2b.3e.4d.5f., 1j.2b.3e.4d.5f., 1p.2b.3e.4d.5f ... 1a.2e.3e.4d.5f., 1b.2e.3e.4d.5f. 1f.2e.3e.4d.5f., 1h.2e.3e.4d.5f., 1j.2e.3e.4d.5f., 1p.2e.3e.4d.5f., a.2f.3e.4d.5f., 1b.2f.3e.4d.5f., 1f.2f.3e.4d.5f, 1h.2f.3e.4d.5f. j.2f.3e.4d.5f .. 1p.2f.3e.4d.5f., 1a.2i.3e.4d.5f., 1b.2i.3e.4d.5f., f.2i.3e. 4d.5f., 1h.2i.3e.4d.5f., 1j.2i.3e.4d.5f., 1 p.2i.3e.4d.5f. a.2m.3e.4d.5f 1b.2m.3e.4d.5f 1f.2m.3e.4d.5f., 1h.2m.3e.4d.5f. j.2m.3e.4d.5f. 1p.2m.3e.4d.5f. 1a.2o.3e.4d.5f., 1b.2o.3e.4d.5f. f.2o.3e.4d.5f. 1h.2o.3e.4d.5f., 1j.2o.3e.4d.5f., 1p.2o.3e.4d.5f. a.2u.3e.4d.5f 1b.2u.3e.4d.5f. 1f.2u.3e.4d.5f., 1h.2u.3e.4d.5f. j.2u.3e.4d.5f 1p.2u.3e.4d.5f., 1a.2y.3e.4d.5f., 1b.2y.3e.4d.5f. f.2y.3e.4d.5f. 1h.2y.3e.4d.5f., 1j.2y.3e.4d.5f., 1p.2y.3e.4d.5f. a.2a.3g.4d.5f 1b.2a.3g.4d.5f. 1f.2a.3g.4d.5f., 1h.2a.3g.4d.5f. j.2a.3g.4d.5f 1p.2a.3g.4d.5f., 1a.2b.3g.4d.5f., 1b.2b.3g.4d.5f. f.2b.3g.4d.5f. 1h.2b.3g.4d.5f. 1j.2b.3g.4d.5f., 1p.2b.3g.4d.5f. a.2e.3g.4d.5f 1b.2e.3g.4d.5f. 1f.2e.3g.4d.5f., 1h.2e.3g.4d.5f. j.2e.3g.4d.5f 1p.2e.3g.4d.5f. 1a.2f.3g.4d.5f., 1b.2f.3g.4d.5f. f.2f.3g.4d.5f., 1h.2f.3g.4d.5f "1j.2f.3g.4d.5f., 1p.2f.3g.4d.5f. a.2i.3g.4d.5f. 1b.2i.3g.4d.5f. 1f.2i.3g.4d.5f., 1h.2i.3g.4d.5f. j.2i.3g.4d.5f., 1p.2i.3g.4d.5f., 1a.2m.3g.4d.5f., 1b.2m.3g.4d.5f. f.2m.3g.4d.5f 1h.2m.3g.4d.5f 1j.2m.3g.4d.5f., 1p.2m.3g.4d.5f. a.2o.3g.4d.5f 1b.2o.3g.4d.5f 1f.2o.3g.4d.5f., 1h.2o.3g.4d.5f. j.2o.3g.4d.5f 1p.2o.3g.4d.5f. 1a.2u.3g.4d.5f., 1b.2u.3g.4d.5f. f.2u.3g.4d.5f. 1h.2u.3g.4d.5f. 1j.2u.3g.4d.5f., 1p.2u.3g.4d.5f. a.2y.3g.4d.5f 1b.2y.3g.4d.5f 1f.2y.3g.4d.5f., 1h.2y.3g.4d.5f. j.2y.3g.4d.5f., 1p.2y.3g.4d.5f. 1a.2a.3a.4f.5f., 1b.2a.3a.4f.5f. f.2a.3a.4f.5f., 1h.2a.3a.4f.5f. 1j.2a.3a.4f.5f., 1p.2a.3a.4f.5f. a.2b.3a.4f.5f 1b.2b.3a.4f.5f. 1f.2b.3a.4f.5f., 1h.2b.3a.4f.5f. 1 j.2b.3a.4f.5f., 1p.2b.3a.4f.5f., 1a.2e.3a.4f.5f., 1b.2e.3a.4f.5f., 1f.2e.3a.4f.5f., 1 h.2e.3a.4f.5f., 1j.2e.3a.4f.5f., 1p.2e.3a.4f.5f. 1a.2f.3a.4f.5f., 1b.2f.3a.4f.5f., 1f.2f.3a.4f.5f., 1 h.2f.3a.4f.5f. 1j.2f.3a.4f.5f., |1p.2f.3a.4f.5f., 1a.2i.3a.4f.5f., 1 b.2i.3a.4f.5f. 1f.2i.3a.4f.5f., 1 h.2i.3a.4f.5f., 1j.2i.3a.4f.5f., 1 p.2i.3a.4f.5f. 1a.2m.3a.4f.5f., 1b.2m.3a.4f.5f., 1f.2m.3a.4f.5f., 1h.2m.3a.4f.5f. 1j.2m.3a.4f.5f., 1p.2m.3a.4f.5f., 1a.2o.3a.4f.5f., 1b.2o.3a.4f.5f. 1f.2o.3a.4f.5f., 1 h.2o.3a.4f.5f., 1j.2o.3a.4f.5f., 1p.2o.3a.4f.5f. 1a.2u.3a.4f.5f., 1 b.2u.3a.4f.5f., 1f.2u.3a.4f.5f., 1h.2u.3a.4f.5f. 1j.2u.3a.4f.5f., 1p.2u.3a.4f.5f., 1a.2y.3a.4f.5f., 1b.2y.3a.4f.5f. 1f.2y.3a.4f.5f., 1 h.2y.3a.4f.5f., 1j.2y.3a.4f.5f., 1p.2y.3a.4f.5f. 1a.2a.3b.4f.5f., 1b.2a.3b.4f.5f., 1f.2a.3b.4f.5f., 1 h.2a.3b.4f.5f. 1j.2a.3b.4f.5f., 1p.2a.3b.4f.5f., 1a.2b.3b.4f.5f., 1b.2b.3b.4f.5f. 1f.2b.3b.4f.5f., 1h.2b.3b.4f.5f., 1j.2b.3b.4f.5f., 1p.2b.3b.4f.5f. 1a.2e.3b.4f.5f., 1b.2e.3b.4f.5f., 1f.2e.3b.4f.5f., 1h.2e.3b.4f.5f. 1j.2e.3b.4f.5f., 1p.2e.3b.4f.5f., 1a.2f.3b.4f.5f., 1 b.2f.3b.4f.5f. 1f.2f.3b.4f.5f., 1 h.2f.3b.4f.5f., 1j.2f.3b.4f.5f., 1p.2f.3b.4f.5f. 1a.2i.3b.4f.5f., 1b.2i.3b.4f.5f., 1f.2i.3b.4f.5f., 1h.2i.3b.4f.5f. 1 j.2i.3b.4f.5f., 1p.2i.3b.4f.5f., 1a.2m.3b.4f.5f., 1b.2m.3b.4f.5f. 1f.2m.3b.4f.5f., 1h.2m.3b.4f.5f., 1j.2m.3b.4f.5f., 1p.2m.3b.4f.5f. 1a.2o.3b.4f.5f., 1b.2o.3b.4f.5f., 1f.2o.3b.4f.5f., 1h.2o.3b.4f.5f. 1j.2o.3b.4f.5f., 1p.2o.3b.4f.5f., 1a.2u.3b.4f.5f., 1b.2u.3b.4f.5f. 1f.2u3b.4f.5f., 1 h.2u.3b.4f.5f., 1j.2u.3b.4f.5f., 1p.2u.3b.4f.5f. 1a.2y.3b.4f.5f., 1b.2y.3b.4f.5f., 1f.2y.3b.4f.5f., 1h.2y.3b.4f.5f. 1j.2y.3b.4f.5f., 1p.2y.3b.4f.5f., 1a.2a.3e.4f.5f., 1b.2a.3e.4f.5f. 1f.2a.3e.4f.5f., 1h.2a.3e.4f5f, 1j.2a.3e.4f.5f., 1 p.2a.3e.4f.5f., 1a.2b.3e.4f.5f., 1b.2b.3e.4f.5f .. 1f.2b.3e.4f.5f., 1h.2b.3e.4f.5f. 1j.2b.3e.4f.5f., 1p.2b.3e.4f.5f, 1a.2e.3e.4f.5f .. 1b.2e.3e.4f.5f, 1f.2e.3e.4f.5f, 1 h.2e.3e.4f.5f., 1j.2e.3e.4f.5f., 1p.2e.3e.4f.5f, 1a.2f.3e.4f.5f .. 1b.2f.3e.4f.5f., 1f.2f.3e.4f.5f., 1h.2f.3e.4f.5f., 1j.2f.3e.4f.5f., 1p.2f.3e.4f.5f., 1a.2i.3e.4f.5f., 1b.2i.3e.4f.5f., 1f.2i.3e.4f.5f., 1 h.2i.3e.4f.5f., 1j.2i.3e.4f.5f., 1p.2i.3e.4f.5f., 1a.2m.3e.4f.5f .. 1b.2m.3e.4f.5f., 1f.2m.3e.4f.5f., 1h.2m.3e.4f.5f., 1j.2m.3e.4f.5f., 1p.2m.3e.4f.5f., 1a.2o.3e.4f.5f., 1b.2o.3e.4f.5f., 1f.2o.3e.4f.5f., 1h.2o.3e.4f.5f., 1j.2o.3e.4f5f, 1p.2o.3e.4f.5f., 1a.2u.3e.4f.5f., 1b.2u.3e.4f.5f., 1f.2u.3e.4f.5f., 1 h.2u.3e.4f.5f., 1j.2u.3e.4f.5f, 1p.2u.3e.4f.5f., Ia.2y.3e.4f.5f., 1b.2y.3e.4f.5f., 1f.2y.3e.4f.5f., 1h.2y.3e.4f.5f., 1j.2y.3e.4f.5f., 1p.2y.3e.4f.5f., 1a.2a.3g.4f.5f., 1b.2a.3g.4f.5f., 1f.2a.3g.4f.5f., 1 h.2a.3g.4f.5f., 1j.2a.3g.4f5f, 1p.2a.3g.4f.5f., 1a.2b.3g.4f.5f., 1b.2b.3g.4f.5f., 1f.2b.3g.4f.5f., 1h.2b.3g.4f.5f., 1j.2b.3g.4f.5f., 1p.2b.3g.4f.5f., 1a.2e.3g.4f.5f, 1b.2e.3g.4f.5f, 1f.2e.3g.4f.5f., 1h.2e.3g.4f.5f., 1j.2e.3g.4f.5f., 1p.2e.3g.4f.5f., 1a.2f.3g.4f.5f., 1b.2f.3g.4f.5f. 1f.2f.3g.4f.5f., 1h.2f.3g.4f.5f, 1j.2f.3g.4f.5f., 1p.2f.3g.4f.5f., 1a.2i.3g.4f.5f., 1b.2i.3g.4f.5f., 1f.2i.3g.4f.5f., 1h.2i.3g.4f.5f., 1j.2i.3g.4f.5f., 1p.2i.3g.4f.5f., 1a.2m.3g.4f.5f., 1b.2m.3g.4f.5f., 1f.2m.3g.4f.5f., 1h.2m.3g.4f.5f., 1j.2m.3g.4f.5f., 1p.2m.3g.4f5f. 1a.2o.3g.4f.5f :, 1b.2o.3g.4f.5f., 1f.2o.3g.4f.5f., 1h.2o.3g.4f.5f., 1j.2o.3g.4f.5f., 1p.2o.3g.4f.5f., 1a.2u.3g.4f.5f., 1 b.2u.3g.4f.5f. 1f.2u.3g.4f.5f, 1h.2u.3g.4f.5f., 1j.2u.3g.4f.5f., 1 p.2u.3g.4f.5f. a.2y.3g.4f.5f., 1b.2y.3g.4f.5f., 1f.2y.3g.4f.5f., 1h.2y.3g.4f.5f., j.2y.3g. 4f.5f, 1p.2y.3g.4f.5f., 1 a.2a.3a.4g.5f., 1b.2a.3a.4g.5f., F2a.3a.4g.5f, 1h.2a. 3a.4g.5f., 1 j.2a.3a.4g.5f., 1p.2a.3a.4g.5f., A.2b.3a.4g.5f., 1b.2b.3a.4g.5f ., 1f.2b.3a.4g.5f., 1h.2b.3a.4g.5f. j.2b.3a.4g.5f, 1p.2b.3a.4g.5f, 1 a.2e.3a.4g.5f, 1b.2e.3a.4g.5f., f.2e.3a.4g. 5f., 1h.2e.3a.4g.5f., 1 j.2e.3a.4g.5f., 1p.2e.3a.4g.5f. a.2f.3a.4g.5f., 1b.2f.3a.4g.5f., 1f.2f.3a.4g.5f., 1 h.2f.3a.4g.5f. j.2f.3a.4g.5f., 1p.2f.3a.4g.5f., 1 a.2i.3a.4g.5f., 1b.2i.3a.4g.5f. f2i.3a.4g.5f., 1 h.2i.3a.4g.5f., 1j.2i.3a.4g.5f., 1 p.2i.3a.4g.5f. a.2m.3a.4g.5f., 1b.2m.3a.4g.5f., 1f.2m.3a.4g.5f., 1h.2m.3a.4g.5f. j.2m.3a.4g.5f., 1 p.2m.3a.4g.5f., 1 a.2o.3a.4g.5f, 1b.2o.3a.4g.5f. f2o.3a.4g.5f., 1h.2o.3a.4g.5f., 1j.2o.3a.4g.5f., 1p.2o.3a.4g.5f. a.2u.3a.4g.5f., 1b.2u.3a.4g.5f., 1f2u.3a.4g.5f., 1h.2u.3a.4g.5f. j.2u.3a.4g.5f., 1 p.2u.3a.4g.5f., 1 a.2y.3a.4g.5f., 1b.2y.3a.4g.5f. f.2y.3a.4g.5f., 1 h.2y.3a.4g.5f., 1j.2y.3a.4g.5f., 1p.2y.3a.4g.5f. a.2a.3b.4g.5f., 1b.2a.3b.4g.5f., 1f2a.3b.4g.5f., 1h.2a.3b.4g.5f. j.2a.3b.4g.5f., 1p.2a.3b.4g.5f., 1a.2b.3b.4g.5f., 1b.2b.3b.4g.5f. f2b.3b.4g.5f., 1h.2b.3b.4g.5f., 1j.2b.3b.4g.5f., 1p.2b.3b.4g.5f. a.2e.3b.4g.5f., 1b.2e.3b.4g.5f., 1f.2e.3b.4g.5f., 1h.2e.3b.4g.5f. j.2e.3b.4g.5f., 1p.2e.3b.4g.5f., 1a.2f3b.4g.5f., 1b.2f.3b.4g.5f. f.2f.3b.4g.5f., 1h.2f.3b.4g.5f., 1j.2f.3b.4g.5f., 1p.2f.3b.4g.5f. a.2i.3b.4g.5f., 1b.2i.3b.4g.5f., 1f.2i.3b.4g.5f., 1h.2i.3b.4g.5f. j.2i.3b.4g.5f., 1p.2i.3b.4g.5f., 1a.2m.3b.4g.5f., 1b.2m.3b.4g.5f. f.2m.3b.4g.5f., 1h.2m.3b.4g.5f., 1j.2m.3b.4g.5f., 1p.2m.3b.4g.5f. a.2o.3b.4g.5f., 1b.2o.3b.4g.5f., 1f.2o.3b.4g.5f., 1h.2o.3b.4g.5f. j.2o.3b.4g.5f., 1p.2o.3b.4g.5f., 1a.2u.3b.4g.5f., 1b.2u.3b.4g.5f., f.2u.3b. 4g.5f., 1h.2u.3b.4g.5f., 1j.2u.3b.4g.5f., 1p.2u.3b.4g.5f., A.2y.3b.4g.5f, 1b. 2y.3b.4g.5f., 1f.2y.3b.4g.5f., 1h.2y.3b.4g.5f., J.2y.3b.4g.5f., 1p.2y.3b.4g. 5f., 1a.2a.3e.4g.5f., 1b.2a.3e.4g.5f., F.2a.3e.4g.5f., 1h.2a.3e.4g.5f., 1j.2a .3e.4g.5f., 1p.2a.3e.4g.5f. a.2b.3e.4g.5f., 1b.2b.3e.4g.5f., 1f.2b.3e.4g.5f., 1h.2b.3e.4g.5f. j.2b.3e.4g.5f., 1p.2b.3e.4g.5f., 1 a.2e.3e.4g.5f., 1b.2e.3e.4g.5f. f.2e.3e.4g.5f., 1h.2e.3e.4g.5f., 1j.2e.3e.4g.5f., 1p.2e.3e.4g.5f. a.2f.3e.4g.5f., 1b.2f.3e.4g.5f., 1f.2f.3e.4g.5f., 1h.2f.3e.4g.5f. j.2f.3e.4g.5f., 1p.2f.3e.4g.5f., 1 a.2i.3e.4g.5f., 1b.2i.3e.4g.5f. f.2i.3e.4g.5f., 1h.2i.3e.4g.5f., 1j.2i.3e.4g.5f., 1 p.2i.3e.4g.5f. a.2m.3e.4g.5f., 1 b.2m.3e.4g.5f., 1f.2m.3e.4g.5f., 1h.2m.3e.4g.5f j.2m.3e.4g .5f., 1 p.2m.3e.4g.5f., 1a.2o.3e.4g.5f., 1b.2o.3e.4g.5f. f.2o.3e.4g.5f., 1h.2o.3e.4g.5f., 1j.2o.3e.4g.5f., 1p.2o.3e.4g.5f. a.2u.3e.4g.5f., 1b.2u.3e.4g.5f., 1f.2u.3e.4g.5f., 1h.2u.3e.4g.5f. j.2u.3e.4g.5f., 1 p.2u.3e.4g.5f., 1 a.2y.3e.4g.5f., 1b.2y.3e.4g.5f. f.2y.3e.4g.5f., 1h.2y.3e.4g.5f., 1j.2y.3e.4g.5f., 1p.2y.3e.4g.5f. a.2a.3g.4g.5f., 1b.2a.3g.4g.5f., 1f.2a.3g.4g.5f., 1h.2a.3g.4g.5f. j.2a.3g.4g.5f., 1 p.2a.3g.4g.5f., 1a.2b.3g.4g.5f., 1b.2b.3g.4g.5f. f.2b.3g.4g.5f., 1h.2b.3g.4g.5f., 1j.2b.3g.4g.5f., 1p.2b.3g.4g.5f. a.2e.3g.4g.5f., 1b.2e.3g.4g.5f., 1f.2e.3g.4g.5f., 1h.2e.3g.4g.5f. j.2e.3g.4g.5f., 1 p.2e.3g.4g.5f., 1a.2f.3g.4g.5f., 1b.2f.3g.4g.5f. f.2f.3g.4g.5f., 1h.2f.3g.4g.5f., 1j.2f.3g.4g.5f., 1p.2f.3g.4g.5f. a.2i.3g.4g.5f., 1b.2i.3g.4g.5f., 1f.2i.3g.4g.5f., 1h.2i.3g.4g.5f. j.2i.3g.4g.5f., 1p.2i.3g.4g.5f., 1a.2m.3g.4g.5f., 1b.2m.3g.4g.5f. 1f.2m.3g.4g.5f., 1h.2m.3g.4g.5f., 1j.2m.3g.4g.5f., 1 p.2m.3g.4g.5f., 1 a.2o.3g.4g.5f., 1b.2o.3g.4g.5f., 1f.2o.3g.4g.5f., 1h.2o.3g.4g.5f., 1j.2o.3g.4g.5f., 1p.2o.3g.4g.5f., 1a.2u.3g.4g.5f., 1b.2u.3g.4g.5f., 1f.2u.3g.4g.5f., 1h.2u.3g.4g.5f., 1j.2u.3g.4g.5f., 1p.2u.3g.4g.5f. 1a.2y.3g.4g.5f., 1b.2y.3g.4g.5f., 1f.2y.3g.4g.5f., 1h.2y.3g.4g.5f. 1j.2y.3g.4g.5f., 1p.2y.3g.4g.5f., 1a.2a.3a.4h.5f., Lb.2a.3a.4h.5f. 1f.2a.3a.4h.5f., 1h.2a.3a.4h.5f., 1j.2a.3a.4h.5f., 1p.2a.3a.4h.5f. 1a.2b.3a.4h.5f., 1b.2b.3a.4h.5f, 1f.2b.3a.4h.5f., 1h.2b.3a.4h.5f. 1j.2b.3a.4h.5f., 1p.2b.3a.4h.5f., 1a.2e.3a.4h.5f., 1b.2e.3a.4h.5f. 1f2e.3a.4h.5f., 1h.2e.3a.4h.5f., 1j.2e.3a.4h.5f., 1p.2e.3a.4h.5f. 1a.2f.3a.4h.5f., 1b.2f.3a.4h.5f., 1f.2f.3a.4h.5f., 1h.2f.3a.4h.5f. 1j.2f.3a.4h.5f., 1p.2f.3a.4h.5f., 1a.2i.3a.4h.5f., 1b.2i.3a.4h.5f. 1f.2i.3a.4h.5f., 1h.2i.3a.4h.5f., 1j.2i.3a.4h.5f., 1p.2i.3a.4h.5f. 1a.2m.3a.4h.5f., 1b.2m.3a.4h.5f., 1f.2m.3a.4h.5f., 1h.2m.3a.4h.5f. 1j.2m.3a.4h.5f., 1p.2m.3a.4h.5f., 1a.2o.3a.4h.5f., 1b.2o.3a.4h.5f. 1f.2o.3a.4h.5f., 1h.2o.3a.4h.5f., 1j.2o.3a.4h.5f., 1p.2o.3a.4h.5f. 1a.2u.3a.4h.5f., 1b.2u.3a.4h.5f., 1f.2u.3a.4h.5f., 1h.2u.3a.4h.5f. 1j.2u.3a.4h.5f., 1p.2u.3a.4h.5f., 1a.2y.3a.4h.5f., 1b.2y.3a.4h.5f. 1f.2y.3a.4h.5f., 1h.2y.3a.4h.5f., 1j.2y.3a.4h.5f., 1p.2y.3a.4h.5f. 1a.2a.3b.4h.5f., 1b.2a.3b.4h.5f., 1f.2a.3b.4h.5f., 1h.2a.3b.4h.5f. 1 j.2a.3b.4h.5f., 1p.2a.3b.4h.5f., 1a.2b.3b.4h.5f., 1b.2b.3b.4h.5f. 1f.2b.3b.4h.5f., 1h.2b.3b.4h.5f., 1j.2b.3b.4h.5f., 1p.2b.3b.4h.5f. 1a.2e.3b.4h.5f., 1b.2e.3b.4h.5f., 1f.2e.3b.4h.5f., 1h.2e.3b.4h.5f. 1j.2e3b.4h.5f., 1p.2e.3b.4h.5f., 1a.2f.3b.4h.5f., 1b.2f.3b.4h.5f. 1f.2f.3b.4h.5f., 1h.2f.3b.4h.5f., 1j.2f.3b.4h.5f., 1p.2f.3b.4h.5f. a.2i.3b.4h.5f., 1b.2i.3b.4h.5f., 1f.2i.3b.4h.5f., 1h.2i.3b.4h.5f. j.2i.3b.4h.5f., 1p.2i.3b.4h.5f, a.2m.3b.4h.5f., 1b.2m.3b.4h.5f. f.2m.3b.4h.5f., 1h.2m.3b.4h.5f. 1j.2m.3b.4h.5f. 1p.2m.3b.4h.5f. a.2o.3b.4h.5f., 1b.2o.3b.4h.5f. 1f.2o.3b.4h.5f. 1h.2o.3b.4h.5f. j.2o.3b.4h.5f., 1p.2o.3b.4h.5f., 1a.2u.3b.4h.5f. 1b.2u.3b.4h.5f. f.2u.3b.4h.5f., 1h.2u.3b.4h.5f. 1j.2u.3b.4h.5f. 1p.2u.3b.4h.5f. a.2y.3b.4h.5f., 1b.2y.3b.4h.5f. 1f.2y.3b.4h.5f. 1h.2y.3b.4h.5f. j.2y.3b.4h.5f., 1p.2y.3b.4h.5f., 1a.2a.3e.4h.5f. 1b.2a.3e; 4h.5f. f.2a.3e.4h.5f., 1h.2a.3e.4h.5f. 1j.2a.3e.4h.5f. 1p.2a.3e.4h.5f. a.2b.3e.4h.5f., 1b.2b.3e.4h.5f. 1f.2b.3e.4h.5f. 1h.2b.3e.4h.5f. j.2b.3e.4h.5f, 1p.2b.3e.4h.5f., 1a.2e.3e.4h.5f. 1b.2e.3e.4h.5f. f.2e.3e.4h.5f., 1h.2e.3e.4h.5f. 1j.2e.3e.4h.5f. 1p.2e.3e.4h.5f. a.2f.3e.4h.5f., 1b.2f.3e.4h.5f. 1f.2f.3e.4h.5f. 1h.2f.3e.4h.5f. j.2f.3e.4h.5f., 1p.2f.3e.4h.5f., 1a.2i.3e.4h.5f. 1b.2i.3e.4h.5f. f.2i.3e.4h.5f., 1h.2i.3e.4h.5f., 1j.2i.3e.4h.5f. 1p.2i.3e.4h.5f. a.2m.3e.4h.5f., 1b.2m.3e.4h.5f 1f.2m.3e.4h.5f 1h.2m.3e.4h.5f. j.2m.3e.4h.5f., 1p.2m.3e.4h.5f 1a.2o.3e.4h.5f 1b.2o.3e.4h.5f. f.2o.3e.4h.5f., 1h.2o.3e.4h.5f. 1j.2o.3e.4h.5f. 1p.2o.3e.4h.5f. a.2u.3e.4h.5f., 1 b.2u.3e.4h.5f 1f.2u.3e.4h.5f. 1h.2u.3e.4h.5f. j.2u.3e.4h.5f., 1p.2u.3e.4h.5f. 1a.2y.3e.4h.5f. 1b.2y.3e.4h.5f. f.2y.3e.4h.5f., 1h.2y.3e.4h.5f. 1j.2y.3e.4h.5f. 1p.2y.3e.4h.5f. a.2a.3g.4h.5f., 1b.2a.3g.4h.5f 1f.2a.3g.4h.5f. 1h.2a.3g.4h.5f. j.2a.3g.4h.5f., 1p.2a.3g.4h.5f. 1a.2b.3g.4h.5f. 1b.2b.3g.4h.5f. f.2b.3g.4h.5f., 1h: 2b.3g.4h.5f. 1j.2b.3g.4h.5f. 1p.2b.3g.4h.5f. a.2e.3g.4h.5f., 1b.2e.3g.4h.5f 1f.2e.3g.4h.5f 1h.2e.3g.4h.5f. j.2e.3g.4h.5f., 1p.2e.3g.4h.5f. 1a.2f.3g.4h.5f., 1b.2f.3g.4h.5f. f.2f.3g.4h.5f., 1h.2f.3g.4h.5f., 1j.2f.3g.4h.5f., 1p.2f.3g.4h.5f. a.2i.3g.4h.5f., 1b.2i.3g.4h.5f. 1f.2i.3g.4h.5f .. 1h.2i.3g.4h.5f. j.2i.3g.4h.5f., 1p.2i.3g.4h.5f., 1a.2m.3g.4h.5f., 1b.2m.3g.4h.5f. f.2m.3g.4h.5f., 1h.2m.3g.4h.5f. 1j.2m.3g.4h.5f., 1p.2m.3g.4h.5f. a.2o.3g.4h.5f., 1b.2o.3g.4h.5f. 1f.2o.3g.4h.5f., 1h.2o.3g.4h.5f. j.2o.3g.4h.5f., 1p.2o.3g.4h.5f. 1a.2u.3g.4h.5f., 1b.2u.3g.4h.5f. f.2u.3g.4h.5f., 1h.2u.3g.4h.5f. 1j.2u.3g.4h.5f., 1p.2u.3g.4h.5f. a.2y.3g.4h.5f., 1b.2y.3g.4h.5f. 1f.2y.3g.4h.5f., 1h.2y.3g.4h.5f. j.2y.3g.4h.5f., 1p.2y.3g.4h.5f. 1a.2a.3a.4i.5f., 1b.2a.3a.4i.5f. f.2a.3a.4i.5f., 1h.2a.3a.4i.5f., 1 j.2a.3a.4i.5f., 1p.2a.3a.4i.5f. a.2b.3a.4i.5f., 1b.'2b.3a.4i.5f. 1f.2b.3a.4i.5f., 1h.2b.3a.4i.5f. j.2b.3a.4i.5f., 1p.2b.3a.4i.5f., 1a.2e.3a.4i.5f., 1b.2e.3a.4i.5f. f.2e.3a.4i.5f., 1h.2e.3a.4i.5f. 1j.2e.3a.4i.5f., 1p.2e.3a.4i.5f. a.2f.3a.4i.5f., 1b.2f3a.4i.5f., 1f.2f.3a.4i.5f., 1h.2f.3a.4i.5f. j.2f.3a.4i.5f., 1p.2f.3a.4i.5f., 1 a.2i.3a.4i.5f., 1b.2i.3a.4i.5f. f.2i.3a.4i.5f., 1h.2i.3a.4i.5f., 1j.2i.3a.4i.5f., 1p.2i.3a.4i.5f. a.2m.3a.4i.5f., 1b.2m.3a.4i.5f 1f.2m.3a.4i.5f., 1h.2m.3a.4i.5f. j.2m.3a.4i.5f., 1 p.2m.3a.4i.5f. 1 a.2o.3a.4i.5f., 1b.2o.3a.4i.5f. f.2o.3a.4i.5f., 1h.2o.3a.4i.5f. 1 j.2o.3a.4i.5f., 1p.2o.3a.4i.5f. a.2u.3a.4i.5f., 1b.2u.3a.4i.5f. 1f.2u.3a.4i.5f., 1h.2u.3a.4i.5f. j.2u.3a.4i.5f., 1p.2u.3a.4i.5f. 1a.2y.3a.4i.5f., 1b.2y.3a.4i.5f. f.2y.3a.4i.5f., 1h.2y.3a.4i.5f. 1j.2y.3a.4i.5f., 1p.2y.3a.4i.5f. a.2a.3b.4i.5f., 1b.2a.3b.4i.5f. 1f.2a.3b.4i.5f., 1h.2a.3b.4i.5f. j.2a.3b.4i.5f., 1p.2a.3b.4i.5f. 1a.2b.3b.4i.5f., 1b.2b.3b.4i.5f. 1f.2b.3b.4i.5f., 1h.2b.3b.4i.5f., 1j.2b.3b.4i.5f., 1p.2b.3b.4i.5f., 1a.2e.3b.4i.5f., 1b.2e.3b.4i.5f., 1f.2e.3b.4i.5f., 1h.2e.3b.4i.5f., 1j.2e.3b.4i.5f., 1p.2e.3b.4i.5f., 1a.2f.3b.4i.5f., 1b.2f.3b.4i.5f., 1f.2f.3b.4i.5f., 1h.2f.3b.4i.5f., 1j.2f.3b.4i.5f., 1p.2f.3b.4i.5f., 1a.2i.3b.4i.5f., 1b.2i.3b.4i.5f., 1f.2i.3b.4i.5f "1 h.2i.3b.4i.5f., 1 j.2i.3b.4i.5f., 1p.2i.3b.4i.5f., 1a.2m.3b.4i.5f., 1b.2m.3b.4i.5f., 1f.2m.3b.4i.5f., 1h.2m.3b.4i.5f. 1j.2m.3b.4i.5f., 1p.2m3b.4i.5f., 1a.2o.3b.4i.5f., 1b.2o.3b.4i.5f., 1f.2o.3b.4i.5f., 1h.2o.3b.4i.5f., 1j.2o.3b.4i.5f., 1 p.2o.3b.4i.5f "1a.2u.3b.4i.5f., 1b.2u.3b.4i.5f., 1f.2u.3b.4i.5f., 1h.2u.3b.4i.5f., 1j.2u.3b.4i.5f., 1p.2u.3b.4i.5f., 1a.2y.3b.4i.5f., 1b.2y.3b.4i.5f., 1f.2y.3b.4i.5f., 1h.2y.3b.4i.5f., 1j.2y.3b.4i.5f., 1p.2y.3b.4i.5f., 1a.2a.3e.4i.5f., 1b 2a.3e.4i.5f., 1f .2a.3e.4i.5f., 1h.2a.3e.4i.5f., 1j.2a.3e.4i.5f., 1p.2a.3e.4i.5f., 1a.2b.3e.4i.5f., 1b.2b.3e.4i.5f. 1f.2b.3e.4i.5f., 1h.2b.3e.4i.5f., 1j.2b.3e.4i.5f., 1p.2b.3e.4i.5f., 1a.2e.3e.4i.5f., 1b.2e.3e.4i.5f., 1f.2e.3e.4i.5f., 1h.2e.3e.4i.5f., 1j.2e.3e.4i.5f., 1p.2e.3e.4i.5f., 1a.2f.3e.4i.5f., 1b.2f.3e.4i.5f., 1f.2f.3e.4i.5f., 1h.2f.3e.4i.5f., 1j.2f.3e.4i.5f., 1p.2f.3e.4i.5f., 1a.2i.3e.4i.5f., 1b.2i.3e.4i.5f., 1f.2i.3e.4i.5f., 1h.2i.3e.4i.5f., 1j.2i.3e.4i.5f., 1p.2i.3e.4i.5f., 1 a.2m.3e.4i.5f. 1b.2m.3e.4i.5f. , 1f.2m.3e.4i.5f., 1h.2m.3e.4i.5f., 1 j.2m.3e.4i.5f., 1 p.2m.3e.4i.5f. 1 a.2o.3e.4i.5f., 1b.2o.3e.4i.5f ... 1f.2o.3e.4i.5f., 1h.2o.3e.4i.5f. 1 j.2o.3e.4i.5f., 1p.2o.3e.4i.5f., 1 a.2u.3e.4i.5f., 1b.2u.3e.4i.5f. 1f.2u.3e.4i.5f., 1h.2u.3e.4i.5f., 1j.2u.3e.4i.5f., 1 p.2u.3e.4i.5f., 1 a.2y.3e.4i.5f., 1b.2y.3e.4i.5f., 1f.2y.3e.4i.5f., 1h.2y.3e.4i.5f., 1j.2y.3e.4i.5f., 1p.2y.3e.4i.5f., a.2a.3g.4i.5f., 1b.2a.3g.4i.5f., 1f.2a.3g.4i.5f., 1 h.2a.3g.4i.5f., j.2a.3g .4i.5f. , 1 p.2a.3g.4i.5f., 1a.2b.3g.4i.5f., 1 b.2b.3g.4i.5f., F.2b.3g.4i.5f., 1h.2b .3g.4i.5f., 1j.2b.3g.4i.5f., 1p.2b.3g.4i.5f., A.2e.3g.4i.5f., 1b.2e.3g.4i.5f ., 1f.2e.3g.4i.5f., 1h.2e.3g.4i.5f., J.2e.3g.4i.5f., 1 p.2e.3g.4i.5f., 1a.2f .3g.4i.5f., 1 b.2f.3g.4i.5f., F.2f.3g.4i.5f., 1 h.2f.3g.4i.5f., 1j.2f.3g.4i .5f., 1p.2f.3g.4i.5f., A.2i.3g.4i.5f., 1b.2i.3g.4i.5f., 1 f .2i.3g.4i.5f. , 1h.2i.3g.4i.5f., J.2i.3g.4i.5f., 1p.2i.3g.4i.5f., 1a.2m.3g.4i.5f., 1b.2m.3g .4i.5f., F.2m.3g.4i.5f., 1h.2m.3g.4i.5f., 1 j.2m.3g.4i.5f., 1p.2m.3g.4i.5f., a.2o.3g.4i.5f., 1b.2o.3g.4i.5f., 1f.2o.3g.4i.5f., 1h.2o.3g.4i.5f., j.2o.3g .4i.5f., 1 p.2o.3g.4i.5f., 1 a.2u.3g.4i.5f., 1b.2u.3g.4i.5f., F.2u.3g.4i.5f ., 1h.2u.3g.4i.5f., 1j.2u.3g.4i.5f., 1p.2u.3g.4i.5f., A.2y.3g.4i.5f., 1b.2y. 3g.4i.5f., 1f.2y.3g.4i.5f., 1h.2y.3g.4i.5f. j.2y.3g.4i.5f .. _ 1 p.2y.3g.4i.5f., 1 a.2a.3a.4a.5g., 1 b.2a.3a.4a.5g. f2a.3a.4a.5g., 1 h.2a.3a.4a.5g., 1 j.2a.3a.4a.5g., 1 p.2a.3a.4a.5g. a.2b.3a.4a.5g., 1b.2b.3a.4a.5g., 1f.2b.3a.4a.5g "1h.2b.3a.4a.5g. j.2b.3a.4a.5g., 1 p.2b.3a.4a.5g., 1 a.2e.3a.4a.5g., 1 b.2e.3a.4a.5g. f.2e.3a.4a.5g., 1 h.2e.3a.4a.5g., 1j.2e.3a.4a.5g., 1 p.2e.3a.4a.5g. a.2f.3a.4a.5g., 1b.2f.3a.4a.5g., 1f.2f.3a.4a.5g., 1h.2f.3a.4a.5g. j.2f.3a.4a.5g., 1 p.2f.3a.4a.5g., 1 a.2i.3a.4a.5g., 1b.2i.3a.4a.5g. f.2i.3a.4a.5g., 1 h.2i.3a.4a.5g., 1j.2i.3a.4a.5g., 1p.2i.3a.4a.5g. a.2m.3a.4a.5g., 1b.2m.3a.4a.5g. , 1f.2m.3a.4a.5g., 1 h.2m.3a.4a.5g. j.2m.3a.4a.5g., 1 p.2m.3a.4a.5g., 1 a.2o.3a.4a.5g., 1 b.2o.3a.4a.5g. f.2o.3a.4a.5g., 1 h.2o.3a.4a.5g., 1 j.2o.3a.4a.5g., 1 p.2o.3a.4a.5g. a.2u.3a.4a.5g., 1 b-2u.3a.4a.5g.,, 1 f.2u.3a.4a.5g., 1 h.2u.3a.4a.5g. j.2u.3a.4a.5g., 1 p.2u.3a.4a.5g., 1 a.2y.3a.4a.5g. , 1 b.2y.3a.4a.5g. f.2y.3a.4a.5g., 1 h.2y.3a.4a.5g. , 1 j.2y.3a.4a.5g., 1 p.2y.3a.4a.5g. a.2a.3b.4a.5g., 1 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a.2u.3a.4f.5g 1 b.2u.3a.4f.5g., 1f.2u.3a.4f.5g. 1h.2u.3a.4f.5g. j.2u.3a.4f.5g. 1 p.2u.3a.4f.5g., 1 a.2y.3a.4f.5g. 1b.2y.3a.4f.5g. f.2y.3a.4f.5g. 1h.2y.3a.4f.5g., 1j.2y.3a.4f.5g. 1p.2y.3a.4f.5g. a.2a.3b.4f.5g 1b.2a.3b.4f.5g., 1f.2a.3b.4f.5g. 1h.2a.3b.4f.5g. j.2a.3b.4f.5g. 1p.2a.3b.4f.5g., 1a.2b.3b.4f.5g. 1b.2b.3b.4f.5g. f.2b.3b.4f.5., 1h.2b.3b.4f.5g., 1j.2b.3b.4f.5g., 1p.2b.3b.4f.5g. a.2e.3b.4f.5g 1b.2e.3b.4f.5g., 1f.2e.3b.4f.5g. 1h.2e.3b.4f.5g. j.2e.3b.4f.5g. 1p.2e.3b.4f.5g., 1a.2f.3b.4f.5g. 1b.2f.3b.4f.5g. f.2f.3b.4f.5g., 1h.2f.3b.4f.5g., 1j.2f.3b.4f.5g. 1p.2f.3b.4f.5g. a.2i.3b.4f.5g. 1b.2i.3b.4f.5g., 1f.2i.3b.4f.5g. 1h.2i.3b.4f.5g. j.2i.3b.4f.5g., 1p.2i.3b.4f.5g., 1a.2m.3b.4f.5g. 1b.2m.3b.4f.5g. f.2m.3b.4f.5g 1h.2m.3b.4f.5g., 1j.2m.3b.4f.5g 1p.2m.3b.4f.5g. a.2o.3b: 4f.5g 1b.2o.3b.4f.5g., .1f.2o.3b.4f.5g 1h.2o.3b.4f.5g. j.2o.3b.4f.5., 1p.2o.3b.4f.5g., 1a.2u.3b.4f.5g. 1b.2u.3b.4f.5g. f.2u.3b.4f.5g. 1h.2u.3b.4f.5g., 1j.2u.3b.4f.5g. 1p.2u.3b.4f.5g. a.2y.3b.4f.5g 1b.2y.3b: 4f.5g., 1f.2y.3b.4f.5g 1h.2y.3b.4f.5g. j.2y.3b.4f.5g. 1p.2y3b.4f.5g., 1a.2a.3e.4f.5g. 1b.2a.3e.4f.5g. f.2a.3e.4f.5g. 1h.2a.3e.4f.5g., 1j.2a.3e.4f.5. 1p.2a.3e.4f.5g. a.2b.3e.4f.5g. 1b.2b.3e.4f.5g., 1f.2b.3e.4f.5g. 1h.2b.3e.4f.5g. j.2b.3e.4f.5g., 1p.2b.3e.4f.5g., 1 a.2e.3e.4f.5., 1b.2e.3e.4f.5g. f.2e.3e.4f.5g. 1h.2e.3e.4f.5g., 1 j.2e.3e.4f.5g. 1p.2e.3e.4f.5g. a.2f.3e.4f.5g. 1b.2f.3e.4f.5., 1f.2f.3e.4f.5g., 1h.2f.3e.4f.5g. j.2f.3e.4f.5g., 1p.2f.3e.4f.5g., 1 a.2i.3e.4f.5g. 1b.2i.3e.4f.5g. f.2i.3e.4f.5g., 1h.2i.3e.4f.5g., 1j.2i.3e.4f.5g., 1p.2i.3e.4f.5g. a.2m.3e.4f.5g 1 b.2m.3e.4f.5g., 1f.2m.3e.4f.5. 1h.2m.3e.4f.5g. j.2m.3e.4f.5g. 1p.2m.3e.4f.5g., 1a.2o.3e.4f.5g 1b.2o.3e.4f.5g. f.2o.3e.4f.5g. 1h.2o.3e.4f.5g., 1j.2o.3e.4f.5g. 1p.2o.3e.4f.5g. a.2u.3e.4f.5g 1b.2u.3e.4f.5g., 1f.2u.3e.4f.5g. 1h.2u.3e.4f.5g. j.2u.3e.4f.5g. 1p.2u.3e.4f.5g., 1 a.2y.3e.4f.5g. 1b.2y.3e.4f.5g. f.2y.3e.4f.5g. 1h.2y.3e.4f.5g., 1j.2y.3e.4f.5g. 1p.2y.3e.4f.5g. a.2a.3g.4f.5g 1b.2a.3g.4f.5g., 1f.2a.3g.4f.5g. 1h.2a.3g.4f.5g. j.2a.3g.4f.5g. 1p.2a.3g.4f.5g., 1a.2b.3g.4f.5g. 1b.2b.3g.4f.5g. f.2b.3g.4f.5g. 1h.2b.3g.4f.5g., 1j.2b.3g.4f.5g. 1p.2b.3g.4f.5g. a.2e.3g.4f.5., 1b.2e.3g.4f.5g., 1f.2e.3g.4f.5g. 1h.2e.3g.4f.5g. j.2e.3g.4f.5g. 1p.2e.3g.4f.5g., 1a.2f.3g.4f.5g 1b.2f.3g.4f.5g. f.2f.3g.4f.5g., 1h.2f.3g.4f.5g., 1j.2f.3g.4f.5g. 1p.2f.3g.4f.5g. a.2i.3g.4f.5g. 1b.2i.3g.4f.5g., 1f.2i.3g.4f.5g. 1h.2i.3g.4f.5g. j.2i.3g.4f.5g., 1p.2i.3g.4f.5., a.2m.3g.4f.5g., 1b.2m.3g.4f.5g. f.2m.3g.4f.5g 1h.2m.3g.4f.5g., 1j.2m.3g.4f.5g 1 p.2m.3g.4f.5g. a.2o.3g.4f.5g 1b.2o.3g.4f.5g., 1f.2o.3g.4f.5g 1h.2o.3g.4f.5g. j.2o.3g.4f.5g. 1p.2o.3g.4f.5g., 1a.2u.3g.4f.5g 1b.2u.3g.4f.5g. f.2u.3g.4f.5g. 1h.2u.3g.4f.5g., 1 j.2u.3g.4f.5g 1p.2u.3g.4f.5g. a.2y.3g.4f.5g 1b.2y.3g.4f.5g., 1f.2y.3g.4f.5g 1h.2y.3g.4f.5g. j.2y.3g.4f.5g., 1p.2y.3g.4f.5g., 1a.2a.3a.4g.5g., 1 b.2a.3a.4g.5. f.2a.3a.4g.5g., 1 h.2a.3a.4g.5g., 1 j.2a.3a.4g.5g., 1 p.2a.3a.4g.5g. a.2b.3a.4g.5g., 1 b.2b.3a.4g.5g., 1f.2b.3a.4g.5g., 1 .2b.3a.4g.5g. j.2b.3a.4g.5g., 1 p.2b.3a.4g.5g., 1 a.2e.3a.4g.5g., 1 b.2e.3a.4g.5g. f.2e.3a.4g.5g., 1 h.2e.3a.4g.5g., 1 j.2e.3a.4g.5g., 1 p.2e.3a.4g.5g. a.2f.3a.4g.5g., 1 b.2f.3a.4g.5g., 1f.2f.3a.4g.5g., 1 h.2f .3a.4g.5g. j.2f.3a.4g.5g., 1p.2f.3a.4g.5g., 1 a.2i.3a.4g.5g., 1 b.2u.3a.4g.5g. f.2i.3a.4g.5g., 1 h.2i.3a.4g.5g., 1j.2i.3a.4g.5g., 1 p.2i.3a.4g.5g. a.2m.3a.4g.5g., 1 b.2m.3a.4g.5g., 1f.2m.3a.4g.5g., 1 h.2m.3a.4g.5g. j.2m.3a.4g.5g., 1 p.2m.3a.4g.5., 1 a.2o.3a.4g.5., 1 b.2o.3a.4g.5g. f.2o.3a.4g.5., 1 h.2o.3a.4g.5g., 1j.2o.3a.4g.5g., 1 p.2o.3a.4g.5g. a.2u.3a.4g.5g., 1 b.2u.3a.4g.5g., 1f.2u.3a.4g.5g., 1 h.2u.3a.4g.5g. j.2u.3a.4g.5g., 1 p.2u.3a.4g.5g., 1a.2y.3a.4g.5g., 1 b.2y.3a.4g.5. f.2y.3a.4g.5g., 1 h.2y.3a.4g.5g., 1j.2y.3a.4g.5g., 1p.2y.3a.4g.5g. a.2a.3b.4g.5g., 1 b.2a.3b.4g.5., 1f.2a.3b.4g.5g., 1 h.2a.3b.4g.5g. j.2a.3b.4g.5g., 1 p.2a.3b.4g.5g., 1a.2b.3b.4g.5g., 1 b.2b.3b.4g.5g. f.2b.3b.4g.5g., 1 h.2b.3b.4g.5g., 1j.2b.3b.4g.5., 1 p.2b.3b.4g.5g. a.2e.3b.4g.5g., 1 b.2e.3b.4g.5., 1f.2e.3b.4g.5g., 1 h.2e.3b.4g.5. j.2e.3b.4g.5g., 1 p.2e.3b.4g.5g., 1a.2f.3b.4g.5g., 1b.2f.3b.4g.5g. f.2f.3b.4g.5g., 1 h.2f.3b.4g.5g., 1j.2f.3b.4g.5g., 1p.2f.3b.4g.5g. a.2i.3b.4g.5g., 1 b.2i.3b.4g.5g., 1f.2i.3b.4g.5g., 1h.2i.3b.4g.5g. j.2i.3b.4g.5g., 1 p.2i.3b.4g.5g., 1a.2m.3b.4g.5g., 1 b.2m.3b.4g.5. f.2m.3b.4g.5g., 1 h.2m.3b.4g.5g., 1j.2m.3b.4g.5g., 1 p.2m.3b.4g.5g. a.2o.3b.4g.5g., 1 b.2o.3b.4g.5g., 1f.2o.3b.4g.5g., 1 h.2o.3b.4g.5g j.2o.3b. 4g.5g., 1 p.2o.3b.4g.5g., 1a.2u.3b.4g.5g., 1 b.2u.3b.4g.5g f.2u.3b.4g.5g., 1 h.2u.3b.4g.5g., 1 j.2u.3b.4g.5g., 1 p.2u.3b.4g.5g. a.2y.3b.4g.5g., 1b.2y.3b.4g.5g., 1f.2y.3b.4g.5g., 1h.2y.3b.4g.5g. j.2y.3b.4g.5g., 1p.2y.3b.4g.5g., 1a.2a.3e.4g.5g., 1 b.2a.3e.4g.5g. f.2a.3e.4g.5g., 1 h.2a.3e.4g.5g., 1 j.2a.3e.4g.5g., 1 p.2a.3e.4g.5g. a.2b.3e.4g.5g., 1b.2b.3e.4g.5g., 1f.2b.3e.4g.5g., 1 h.2b.3e.4g.5g. j.2b.3e.4g.5g., 1p.2b.3e.4g.5g., 1a.2e.3e.4g.5g., 1 b.2e.3e.4g.5g. f.2e.3e.4g.5g., 1 h.2e.3e.4g.5g., 1 j.2e.3e.4g.5g., 1 p.2e.3e.4g.5g. a.2f.3e.4g.5g., 1b.2f.3e.4g.5g., 1f.2f.3e.4g.5g., 1 h.2f.3e.4g.5g. j.2f.3e.4g.5g., 1p.2f.3e.4g.5g., 1 a.2i.3e.4g.5g., 1 b.2i.3e.4g.5g. f.2i.3e.4g.5g., 1 h.2i.3e.4g.5g., 1j.2i.3e.4g.5g., 1p.2i.3e.4g.5g. a.2m.3e.4g.5g., 1 b.2m.3e.4g.5g., 1f.2m.3e.4g.5g., 1 h.2m.3e.4g.5g. j.2m.3e.4g.5g., 1 p.2m.3e.4g.5g., 1 a.2o.3e.4g.5g., 1 b.2o.3e.4g.5g. f.2o.3e, 4g.5g., 1 h.2o.3e.4g.5g., 1j.2o.3e.4g.5g., 1 p.2o.3e.4g.5g. a.2u.3e.4g.5g., 1b.2u.3e.4g.5g., 1f.2u.3e.4g.5g., 1 h.2u.3e.4g.5g. j.2u.3e.4g.5g., 1 p.2u.3e.4g.5g., 1a.2y.3e.4g.5g., 1 b.2y.3e.4g.5g. f.2y.3e.4g.5g., 1h.2y.3e.4g.5g., 1j.2y.3e.4g.5g., 1 p.2y.3e.4g.5g. a.2a.3g.4g.5g., 1b.2a.3g.4g.5g., 1f.2a.3g.4g.5g., 1 h.2a.3g.4g.5g. j.2a.3g.4g.5g., 1p.2a.3g.4g.5g., 1a.2b.3g.4g.5g., 1 b.2b.3g.4g.5g. f.2b.3g.4g.5g., 1h.2b.3g.4g.5g., 1j.2b.3g.4g.5g., 1 p.2b.3g.4g.5g. a.2e.3g.4g.5g., 1b.2e.3g.4g.5g., If.2e3g.4g.5g., 1 h.2e.3g.4g.5g. j.2e.3g.4g.5g., 1p.2e.3g.4g.5g., 1a.2f.3g.4g.5g., 1b.2f.3g.4g.5g. f.2f.3g.4g.5g., lh.2f.3g.4g.5g., 1j.2f.3g.4g.5g., 1p.2f.3g.4g.5g. a.2i.3g.4g.5g., 1b.2i.3g.4g.5g., 1f.2i.3g.4g.5g., 1 h.2i.3g.4g.5g. j.2i.3g.4g.5g., 1p.2i.3g.4g.5g., 1a.2m.3g.4g.5g., 1 b.2m.3g.4g.5g. f.2m.3g.4g.5g., 1h.2m.3g.4g.5g., 1j.2m.3g.4g.5g., 1 p.2m.3g.4g.5g. a.2o.3g.4g.5g., 1b.2o.3g.4g.5g., 1f.2o.3g.4g.5g., 1 h.2o.3g.4g.5g. j.2o.3g.4g.5g., 1 p.2o.3g.4g.5g., 1a.2u.3g.4g.5., 1 b.2u.3g.4g.5g. f.2u.3g.4g.5g., 1 h.2u.3g.4g.5g., 1j.2u.3g.4g.5g., 1 p.2u.3g.4g.5g. a.2y.3g.4g.5g., 1 b.2y.3g.4g.5g., 1f.2y.3g.4g.5g., 1 h.2y.3g.4g.5g. j.2y.3g.4g.5g., 1 p.2y.3g.4g.5g., 1a.2a.3a.4h.5g., 1 b.2a.3a.4h.5g. f.2a.3a.4h.5., 1 h.2a.3a.4h.5g., 1j.2a.3a.4h.5g., 1 p.2a.3a.4h.5g. a.2b.3a.4h.5g., 1 b.2b.3a.4h.5g., 1f.2b.3a.4h.5g., 1 h.2b.3a.4h.5g. j.2b.3a.4h.5g., 1 p.2b.3a.4h.5g., 1a.2e.3a.4h.5g., 1 b.2e.3a.4h.5g. f.2e.3a.4h.5g., 1 h.2e.3a.4h.5g., 1 j.2e.3a.4h.5g., 1 p.2e.3a.4h.5g: a.2f. 3a.4h.5g., 1 b.2f.3a.4h.5g., 1f.2f.3a.4h.5g., 1 h.2f.3a.4h.5. j.2f.3a.4h.5g., 1 p.2f.3a.4h.5., 1a.2i.3a.4h.5g., 1 b.2i.3a.4h.5g. f.2i.3a.4h.5g., 1 h.2i.3a.4h.5g., 1j.2i.3a.4h.5., 1 p.2i.3a.4h.5g. a.2m.3a.4h.5., 1 b.2m.3a.4h.5g., 1f.2m.3a.4h.5g., 1 h.2m.3a.4h.5g. j.2m.3a.4h.5g., 1 p.2m.3a.4h.5g., 1a.2o.3a.4h.5g., 1 b.2o.3a.4h.5g. f.2o.3a.4h.5g., 1 h.2o.3a.4h.5g., 1j.2o.3a.4h.5g., 1 p.2o.3a.4h.5. a.2u.3a.4h.5g., 1 b.2u.3a.4h.5g., 1f.2u.3a.4h.5g., 1h.2u.3a.4h.5g. j.2u.3a.4h.5g., 1 p.2u.3a.4h.5g., 1a.2y.3a.4h.5g., 1 b.2y.3a.4h.5g. f.2y.3a.4h.5g., 1 h.2y.3a.4h.5g., 1j.2y.3a.4h.5g., 1 p.2y.3a.4h.5g. a.2a.3b.4h.5g., Ib.2a.3b.4h3g.,. 1f.2a.3b.4h.5., 1 h.2a.3b.4h.5g. j.2a.3b.4h.5g., 1 p.2a.3b.4h.5g., 1a.2b.3b.4h.5g., 1 b.2b.3b.4h.5g. f.2b.3b.4h.5g., 1h.2b.3b.4h.5g., 1j.2b.3b.4h.5g., 1 p.2b.3b.4h.5g. a.2e.3b.4h.5g., 1 b.2e.3b.4h .5g., 1f.2e.3b.4h.5g., 1 h.2e.3b.4h.5g. j.2e.3b.4h.5g., 1 p.2e.3b.4h.5g., 1a.2f.3b.4h.5g., 1 b.2f.3b.4h.5g. f.2f.3b.4h.5g., 1 h.2f.3b.4h.5g., 1j.2f.3b.4h.5g., 1 p.2f.3b.4h.5g a.2i.3b. 4h.5g., 1 b.2i.3b.4h.5g., 1f.2i.3b.4h.5g., 1 h.2i.3b.4h.5g j.2i.3b.4h.5g., 1 p.2i.3b.4h.5g., 1 a.2m.3b.4h.5g., 1 b.2m.3b.4h.5g. f.2m.3b.4h.5g., 1 h.2m.3b.4h.5g., 1j.2m.3b.4h.5., 1 p.2m.3b.4h.5g. a.2o.3b.4h.5g., 1 b.2o.3b.4h.5g., 1f.2o.3b.4h.5g., 1 h.2o.3b.4h.5g. j.2o.3b.4h.5g., 1 p.2o.3b.4h.5g., 1a.2u.3b.4h.5g., 1 b.2u.3b.4h.5g. f.2u.3b.4h.5g., 1h.2u.3b.4h.5g., 1j.2u.3b.4h.5g., 1 p.2u.3b.4h.5g. a.2y.3b.4h.5g., 1 b.2y.3b.4h.5g., 1f.2y.3b.4h.5g., 1h.2y.3b.4h.5. j.2y.3b.4h.5g., 1 p.2y.3b.4h.5g., 1a.2a.3e.4h.5g., 1 b.2a.3e.4h.5g. f.2a.3e.4h.5g., 1 h.2a.3e.4h.5., 1 j.2a.3e.4h.5g., 1 p.2a.3e.4h.5g. a.2b.3e.4h.5g., 1 b.2b.3e.4h.5g., 1f.2b.3e.4h.5g., 1 h.2b.3e.4h.5g. j.2b.3e.4h.5g., 1 p.2b.3e.4h.5g., 1a.2e.3e.4h.5g., 1 b.2e.3e.4h.5g. f.2e.3e.4h.5g., 1 h.2e.3e.4h.5g., 1 j.2e.3e.4h.5g., 1 p.2e.3e.4h.5g. a.2f.3e.4h.5g., 1 b.2f.3e.4h.5g., 1f.2f.3e.4h.5g., 1 h.2f.3e.4h.5g. j.2f.3e.4h.5g., 1 p.2f.3e.4h.5g., 1 a.2i.3e.4h.5g., 1 b.2i.3e.4h.5g. f.2i.3e.4h.5g., 1 h.2i.3e.4h.5g., 1j.2i.3e.4h.5g., 1 p.2i.3e.4h.5g. a.2m.3e.4h.5g., 1 b.2m.3e.4h.5g., 1f.2m.3e.4h.5g., 1 h.2m.3e.4h.5g. j.2m.3e.4h.5g., 1 p.2m.3e.4h.5., 1a.2o.3e.4h.5g., 1 b.2o.3e.4h.5. f.2o.3e.4h.5g., 1 h.2o.3e.4h.5g., 1j.2o.3e.4h.5g., 1p.2o.3e.4h.5g. a.2u.3e.4h.5g., 1b.2u.3e.4h.5g., 1f.2u.3e.4h.5g., 1h.2u.3e.4h.5g. j.2u.3e.4h.5g., 1 p.2u.3e.4h.5g., 1a.2y.3e.4h.5g., 1 b.2y.3e.4h.5g. f.2y.3e.4h.5g., 1 h.2y.3e.4h.5g., 1j.2y.3e.4h.5g., 1 p.2y.3e.4h.5g. a.2a.3g.4h.5g., 1 b.2a.3g.4h .5g., 1f.2a.3g.4h.5g., 1 h.2a.3g.4h.5g. j.2a.3g.4h.5g., 1 p.2a.3g.4h.5g., 1a.2b.3g.4h.5g., 1 b.2b.3g.4h.5g. f.2b.3g.4h.5g., 1 h.2b.3g.4h.5g., 1j.2b.3g.4h.5g., 1 p.2b.3g.4h.5g. a.2e.3g.4h.5g., 1 b.2e.3g.4h .5g. , 1f.2e.3g.4h.5g., 1 h.2e.3g.4h.5g. j.2e.3g.4h.5g., 1 p.2e.3g.4h .5g., 1a.2f.3g.4h.5g., 1 b.2f.3g.4h.5g f.2f.3g.4h.5g., 1h.2f.3g.4h.5g., 1j.2f.3g.4h.5g., 1p.2f.3g.4h.5g. a.2i.3g.4h.5g. 1b.2i.3g.4h.5g., 1f.2i.3g.4h.5g., 1h.2i.3g.4h.5g. j.2¡.3g.4h.5g., 1 p.2i.3g.4h.5g., 1 a.2m.3g.4h.5g., 1 b.2m.3g.4h.5g. f.2m.3g.4h.5g 1 h.2m.3g.4h.5g., 1j.2m.3g.4h.5g., 1 p.2m.3g.4h.5g. a.2o.3g.4h.5g 1b.2o.3g.4h.5g., 1f.2o.3g.4h.5g., 1h.2o.3g.4h.5. j.2o.3g.4h.5g. 1p.2o.3g.4h.5g., 1a.2u.3g.4h.5g., 1b.2u.3g.4h.5. f.2u.3g.4h.5g. 1h.2u.3g.4h.5g., 1j.2u.3g.4h.5g., 1p.2u.3g.4h.5g. a.2y.3g.4h.5g 1b.2y.3g.4h.5g., 1f.2y.3g.4h.5g., 1h.2y.3g.4h.5g. j.2y.3g.4h.5g. 1p.2y.3g.4h.5g., 1a.2a.3a.4i.5g., 1b.2a.3a.4i.5g. f.2a.3a.4i.5g., 1 h.2a.3a.4i.5g., 1j.2a.3a.4i.5g., 1p.2a.3a.4i.5g. a.2b.3a.4i.5g. 1b.2b.3a.4i.5g., 1f.2b.3a.4i.5g., 1h.2b.3a.4i.5g. j.2b.3a.4i.5g., 1 p.2b.3a.4i.5g., 1 a.2e.3a.4i.5g., 1b.2e.3a.4i.5g. f.2e.3a.4i.5g., 1 h.2e.3a.4i.5., 1 j.2e.3a.4i.5g., 1p.2e.3a.4i.5g. a.2f.3a.4i.5g., 1b.2f.3a.415g., 1f.2f.3a.4i.5., 1h.2f.3a.4i.5g. j.2f.3a.4i.5g., 1 p.2f.3a.4i.5g., 1a.2i.3a.4i.5g., 1b.2i.3a.4i.5g. f.2i.3a.4i.5g., 1 h.2i.3a.4i.5g., 1j.2i.3a.4i.5g., 1 p.2i.3a.4i.5. a.2m.3a.4i.5g 1b.2m.3a.4i.5g., 1f.2m.3a.4i.5g., 1h.2m.3a.4i.5. j.2m.3a.4i.5g. 1 p.2m.3a.4i.5g., 1a.2o.3a.4i.5g., 1b.2o.3a.4i.5. f.2o.3a.4i.5g. 1 h.2o.3a.4i.5., 1 j.2o.3a.4i.5g., 1p.2o.3a.4i.5g. a.2u.3a.4i.5g 1 b.2u.3a.4i.5g., 1f.2u.3a.4i.5g., 1 h.2u.3a.4i.5g. j.2u.3a.4i.5g. 1 p.2u.3a.4i.5g., 1a.2y.3a.4i.5., 1 b.2y.3a.4i.5g. f.2y.3a.4i.5g. 1 h.2y.3a.4i.5g., 1j.2y.3a.4i.5g., 1 p.2y.3a.4i.5g. a.2a.3b.4i.5g 1b.2a.3b.4i.5g., 1f.2a.3b.4i.5g., 1h.2a.3b.4i.5g. j.2a.3b.4i.5g. 1 p.2a.3b.4i.5g., 1a.2b.3b.4i.5g., 1b.2b.3b.4i.5g. f.2b.3b.4i.5g. 1 h.2b.3b.4i.5g., 1j.2b.3b.4i.5g., 1p.2b.3b.4i.5g. 1 a.2e.3b.4¡.5g., 1b.2e, 3b.4i.5g., 1f.2e.3b.4i.5g., 1h.2e.3b.4i 5g. 1 j.2e.3b.4i.5g., 1 p.2e.3b.4i.5g., 1a.2f.3b.4i.5g., 1b.2f.3b.4i 5g. 1f.2f.3b.4i.5g., 1h.2f.3b.4i.5g., 1j.2f.3b.4i.5g.i 1p.2f.3b.4i 5g. 1a.2i.3b.4i.5g., 1b.2i.3b.4i.5g., 1f.2i.3b.4i.5g., 1h.2i.3b.4i 5g. 1j.2i.3b.4i.5g., 1p.2i.3b.4i.5g., 1a.2m.3b.4i.5g., 1b.2m.3b.4i • 5g. 1f.2m.3b.4i.5g., 1 h.2m.3b.4i.5g. 1j.2m.3b.4i.5., 1 p.2m.3b.4i • 5g. 1a.2o ÷ 3b.4¡.5g., 1 b.2o.3b.4i.5g., 1f.2o.3b.4i.5g., 1h.2o.3b.4i .5g. 1j.2o.3b.4i.5g., 1p.2o.3b.4i.5g., 1a.2u.3b.4i.5., 1b.2u.3b.4i | 5g. 1f.2u.3b.4i.5g., 1h.2u.3b.4i.5g., 1j.2u.3b.4i.5g., 1p.2u.3b.4i | 5g. 1a.2y.3b.4i.5g., 1 b.2y.3b.4i.5g., 1f.2y.3b.4i.5g., 1h.2y.3b.4i • 5g. 1 j.2y.3b.4i.5g., 1 p.2y.3b.4i.5g., 1a.2a.3e.4i.5g., 1b.2a.3e.4i • 5g. 1 f.2a.3e.4i.5g., 1 h.2a.3e.4i.5g., 1j.2a.3e.4i.5g., 1p.2a.3e.4i | 5g. 1a.2b.3e.4i.5g., 1b.2b.3e.4i.5g., 1f.2b.3e.4i.5g., 1h.2b.3e.4i • 5g. 1j.2b.3e.4i.5g., 1 p.2b.3e.4i.5g., 1 a.2e.3e.4i.5., 1b.2e.3e.4i | 5g. 1f.2e.3e.4i.5., 1 h.2e.3e.4i.5g., 1 j.2e.3e.4i.5g., 1 p.2e.3e.4i • 5g. 1 a.2f.3e.4i.5g., 1b.2f.3e.4i.5g., 1f.2f.3e.4i.5g., 1h.2f.3e.4i • 5g. 1j.2f.3e.4i.5g., 1 p.2f.3e.4i.5g., 1 a.2i.3e.4i.5., 1b.2i.3e.4i • 5g. 1f.2i.3e.4i.5g., 1 h.2i.3e.4i.5g., 1j.2i.3e.4i.5g., 1p.2i.3e.4i | 5g. 1 a.2m.3e.4i.5g. 1 b.2m.3e.4i.5g. , 1f.2m.3e.4i.5g., 1h.2m.3e.4i • 5g. 1 j.2m.3e.4i.5g., 1p.2m.3e.4i.5g. 1 a.2o.3e.4i.5g., 1b.2o.3e.4i • 5g. 1f.2o.3e.4i.5g., 1 h.2o.3e.4i.5g., 1j.2o.3e.4i.5g., 1 p.2o.3e.4 |5g. 1 a.2u.3e.4i.5g., 1b.2u.3e.4i.5g. 1 f.2u.3e.4i.5g. 1h.2u.3e.4i.5. 1 j.2u.3e.4i.5g., 1p.2u.3e.4i.5g., 1a.2y.3e.4i.5g., 1 b.2y.3e.4i.5g 1f.2y.3e.4i.5g., 1 h.2y.3e.4i.5g., 1j.2y.3e.4i.5g., 1 p.2y.3e.4i.5g 1 a.2a.3g.4i.5g., 1 b.2a.3g.4i.5g. , 1f.2a.3g.4i.5g., 1 h.2a.3g.4i.5g 1j.2a.3g.4i.5g., 1p.2a.3g.4i.5g., 1a.2b.3g.4i.5g., 1b.2b.3g.4i.5g. 1f.2b.3g.4i.5g., 1 h.2b.3g.4i.5g., 1j.2b.3g.4i.5g., 1p.2b.3g.4i.5g. 1 a.2e.3g.4i.5g., 1b.2e.3g.4i.5g., 1f.2e.3g.4i.5g., 1h.2e.3g.4i.5g. 1j.2e.3g.4i.5g., 1 p.2e.3g.4i.5g., 1a.2f.3g.4i.5g., 1b.2f.3g.4i.5g. 1f.2f.3g.4i.5g., 1 h.2f.3g.4i.5g., 1j.2f.3g.4i.5g., 1p.2f.3g.4i.5g. 1a.2i.3g.4i.5g., 1 b.2i.3g.4i.5g., 1f.2i.3g.4i.5g., 1 h.2i.3g.4i.5g. 1j.2i.3g.4i.5g., 1p.2i.3g.4i.5., 1 a.2m.3g.4i.5g., 1 b.2m.3g.4i.5g. 1f.2m.3g.4i.5g., 1 h.2m.3g.4i.5g., 1j.2m.3g.4i.5g., 1 p.2m.3g.4i.5g. 1 a.2o.3g.4i.5g., 1b.2o.3g.4i.5g., 1f.2o.3g.4i.5g., 1 h.2o.3g.4i.5g. 1j.2o.3g.4i.5g., 1p.2o.3g.4i.5g., 1a.2u.3g.4i.5g., 1b.2u.3g.4i.5g. 1f.2u.3g.4i.5g., 1 h.2u.3g.4i.5g., 1 j.2u.3g.4i.5., 1 p.2u.3g.4i.5g. 1a.2y.3g.4i.5g., 1b.2y.3g.4i.5g., 1f.2y.3g.4i.5g., 1 h.2y.3g.4i.5g. 1j.2y.3g.4i.5g., 1p.2y.3g.4i.5g., 1a.2a.3a.4a.5h., 1b.2a.3a.4a.5h. 1f.2a.3a.4a.5h., 1 h.2a.3a.4a.5., 1j.2a.3a.4a.5h., 1p.2a.3a.4a.5. 1a.2b.3a.4a.5h., 1b.2b.3a.4a.5., 1f.2b.3a.4a.5h., 1h.2b.3a.4a.5h. 1j.2b.3a.4a.5h., 1p.2b.3a.4a.5., 1 a.2e.3a.4a.5h., 1b.2e.3a.4a.5h 1f.2e.3a.4a.5h., 1h.2e.3a.4a.5h. , 1j.2e.3a.4a.5h., 1p.2e.3a.4a.5h 1a.2f.3a.4a.5h., 1b.2f.3a.4a.5., 1f.2f.3a.4a.5h., Lh.2f.3a.4a.5h. 1j.2f.3a.4a.5h., 1p.2f.3a.4a.5h., 1 a.2i.3a.4a.5h., 1b.2i.3a.4a.5h 1f.2i.3a.4a.5h., 1h.2i.3a.4a.5h., 1j.2i.3a.4a.5h., 1 p.2i.3a.4a.5h 1 a.2m.3a.4a.5h. , 1 b.2m.3a.4a.5.,, 1 f.2m.3a.4a.5h., 1 h.2m.3a.4a.5h 1 j.2m.3a.4a.5., 1p.2m.3a.4a.5., 1 a.2o.3a.4a.5h., 1 b.2o.3a.4a.5 1 f.2o.3a.4a.5., 1h.2o.3a.4a.5h., 1j.2o.3a.4a.5h., 1 p.2o.3a.4a.5h 1 a.2u.3a.4a.5h., 1b.2u.3a.4a.5h. , 1f.2u.3a.4a.5h., 1h.2u.3a.4a.5h 1 j.2u.3a.4a.5h., 1 p.2u.3a.4a.5., 1 a.2y.3a.4a.5h., 1b.2y.3a.4a.5h f.2y.3a.4a.5h., 1 h.2y.3a.4a.5h., 1 j.2y.3a.4a.5h., 1 p.2y.3a.4a.5h. a.2a.3b.4a.5h.p 1 b.2a.3b.4a.5h. , 1 f.2a.3b.4a.5h. , 1h.2a'.3b.4a.5h. j.2a.3b.4a.5h., 1 p.2a.3b.4a.5h., 1 a.2b.3b.4a.5h., 1 b.2b.3b.4a.5h. f.2b.3b.4a.5h., 1 h.2b.3b.4a.5h., 1j.2b.3b.4a.5., 1 p.2b.3b.4a.5h. a.2e.3b.4a.5h., 1 b.2e.3b.4a.5h., 1 f.2e.3b.4a.5., 1 h.2e.3b.4a.5h. j.2e.3b.4a.5h., 1 p.2e.3b.4a.5h., 1 a.2f.3b.4a.5h., 1 b.2f .3b.4a.5h. f.2f.3b.4a.5h., 1h.2f.3b.4a.5h., 1 j.2f.3b.4a.5h., 1 p.2f .3b.4a.5h. a.213b.4a.5h., 1 b.2i.3b.4a.5h., 1 f.2i.3b.4a.5h., 1 h.2i.3b.4a.5h. j.2i.3b.4a.5h., 1 p.2i.3b.4a.5h., 1 a.2m.3b.4a.5h., 1 b.2m.3b.4a.5h. f.2m.3b.4a.5h., 1 h.2m.3b.4a.5h., 1 j.2m.3b.4a.5h., 1p.2m.3b.4a.5h. a.2o.3b.4a.5h., 1 b.2o.3b.4a.5h., 1 f.2o.3b.4a.5h., 1 h.2o.3b.4a.5h. j.2o.3b.4a.5h., 1 p.2o.3b.4a.5h., 1 a.2u.3b.4a.5h., 1 b.2u.3b.4a.5h. f.2u.3b.4a.5h., 1h.2u.3b.4a.5h., 1 j.2u.3b.4a.5h., 1 p.2u.3b.4a.5h. a.2y.3b.4a.5h., 1 b.2y.3b.4a.5h., 1 f.2y.3b.4a.5h., 1 h.2y.3b.4a.5h. j.2y.3b.4a.5h., 1p.2y.3b.4a.5h., 1 a.2a.3e.4a.5h., 1 b.2a.3e.4a.5h. f.2a.3e.4a.5h., 1 h.2a.3e.4a.5h., 1 j.2a.3e.4a.5h., 1 p.2a.3e.4a.5h. a.2b.3e.4a.5h., 1 b.2b.3e.4a.5h., 1f.2b.3e.4a.5h., 1 h.2b.3e.4a.5h. j.2b.3e.4a.5h., 1 p.2b.3e.4a.5h., 1 a.2e.3e.4a.5h., 1 b.2e.3e.4a.5h. f.2e.3e.4a.5h., 1 h.2e.3e.4a.5., 1 j.2e.3e.4a.5h., 1 p.2e.3e.4a.5h. a.2f.3e.4a.5h., 1 b.2f.3e.4a.5h., 1 f.2f.3e.4a.5h., 1 h.2f.3e.4a.5. j.2f.3e.4a.5h., 1 p.2f.3e.4a.5., 1 a.2i.3e.4a.5h., 1b.2i.3e.4a.5h f.2i.3e. 4a.5h., 1 h.2L3e.4a.5h., 1 j.2i.3e.4a.5h., 1 p.2i.3e.4a.5h a.2m.3e.4a.5h., 1 b .2m.3e.4a.5h., 1 f .2m.3e.4a.5h., 1 h.2m .3e.4a.5h j.2m.3e.4a.5h., 1 p.2m.3e. 4a.5h., 1 a.2o.3e.4a.5h., 1 b.2o.3e.4a.5h f.2o.3e.4a.5h., 1 h.2o.3e.4a.5h., 1 j.2o.3e.4a.5h., 1 p.2o.3e.4a.5h a.2u.3e.4a.5h., 1 b.2u.3e.4a.5h., 1 f .2u.3e.4a.5h. 1h.2u.3e.4a.5h. j.2u.3e.4a.5h., 1 p.2u.3e.4a.5h., 1 a.2y.3e.4a.5h. 1b.2y.3e.4a.5h. f.2y.3e.4a.5h., 1 h.2y.3e.4a.5., 1 j.2y.3e.4a.5h. 1p.2y.3e.4a.5h. a.2a.3g.4a.5h., 1 b.2a.3g.4a.5h., 1f.2a.3g.4a.5., 1h.2a.3g.4a.5h. j.2a.3g.4a.5., 1 p.2a.3g.4a.5h., 1 a.2b.3g.4a.5h., 1b.2b.3g.4a.5h. f.2b.3g.4a.5h., 1 h.2b.3g.4a.5h., 1 j.2b.3g.4a.5., 1p.2b.3g.4a.5h. a.2e.3g.4a.5h., 1 b.2e.3g.4a.5h., 1f.2e.3g.4a.5h. 1h.2e.3g.4a.5h. j.2e.3g.4a.5h., 1 p.2e.3g.4a.5h., 1 a.2f.3g.4a.5h. 1b.2f.3g.4a.5h. f.2f.3g.4a.5h., 1 h.2f.3g.4a.5h., 1 j.2f.3g.4a.5h., 1p.2f.3g.4a.5h. a.2i.3g.4a.5h., 1 b.2i.3g.4a.5h., 1f.2i.3g.4a.5h. 1h.2i.3g.4a.5h. j.2i.3g.4a.5h., 1 p.2i.3g.4a.5h., 1 a.2m.3g.4a.5h., 1b.2m.3g.4a.5h. f.2m.3g.4a.5h., 1 h.2m.3g.4a.5h., 1 j.2m.3g.4a.5h. 1 p.2m.3g.4a.5h. a.2o.3g.4a.5h., 1 b.2o.3g.4a.5h., 1 f .2o.3g.4a.5h. 1h.2o.3g.4a.5h. j.2o.3g.4a.5h., 1 p.2o.3g.4a.5h., 1 a.2u.3g.4a.5h 1 b.2u.3g.4a.5. f.2u.3g.4a.5h., 1 h.2u.3g.4a.5., 1 j.2u.3g.4a.5h., 1 p.2u.3g.4a.5h. a.2y.3g.4a.5h., 1 b.2y.3g.4a.5h., 1 f.2y.3g.4a.5h. 1h.2y.3g.4a.5h; j.2y.3g.4a.5h., 1 p.2y.3g.4a.5h., 1 a.2a.3a.4d.5h. 1b.2a.3a.4d.5h. f.2a.3a.4d.5h., 1 h.2a.3a.4d.5., 1 j.2a.3a.4d.5h. 1p.2a.3a.4d.5. a.2b.3a.4d.5h., 1 b.2b.3a.4d.5h., 1f.2b.3a.4d.5h. 1 .2b.3a.4d.5h. j.2b.3a.4d.5h., 1 p.2b.3a.4d.5h., 1 a.2e.3a.4d.5h. 1b.2e.3a.4d.5h. f.2e.3a.4d.5h., 1 h.2e.3a.4d.5h., 1 j.2e.3a.4d.5h. 1p.2e.3a.4d.5h. a.2f.3a.4d.5h., 1 b.2f.3a.4d.5h., 1 f .2f .3a.4d.5h. 1h.2f.3a.4d.5h. j.2f.3a.4d.5h., 1 p.2f.3a.4d.5h., 1 a.2i.3a.4d.5h 1b.2i.3a.4d.5. f.2i.3a.4d.5h., 1 h.2i.3a.4d.5h., 1 j.2i.3a.4d.5h. 1p.2i.3a.4d.5h. a.2m.3a.4d.5h., 1 b.2m.3a.4d.5h., 1f.2m.3a.4d.5h 1h.2m.3a.4d.5h. j.2m.3a.4d.5h., 1 p.2m.3a.4d.5h., 1 a.2o.3a.4d.5h., 1b.2o.3a.4d.5h. f.2o.3a.4d.5h., 1h.2o.3a.4d.5h., 1j.2o.3a.4d.5h., 1p.2o.3a.4d.5h a.2u.3a.4d. 5h., 1b.2u.3a.4d.5h., 1f.2u.3a.4d.5h., 1h.2u.3a.4d.5h j.2u.3a.4d.5h., 1p.2u.3a .4d.5h., 1a.2y.3a.4d.5h., 1b.2y.3a.4d.5h f.2y.3a.4d.5h., 1h.2y.3a.4d.5h., 1j. 2y.3a.4d.5h., 1p.2y.3a.4d.5h a.2a.3b.4d.5h., 1b.2a.3b.4d.5h., 1f.2a.3b.4d.5h. , 1h.2a.3b.4d.5h j.2a.3b.4d.5h., 1p.2a.3b.4d.5h., 1a.2b.3b.4d.5h., 1b.2b.3b.4d .5h f.2b.3b.4d.5h., 1h.2b.3b.4d.5h., 1j.2b.3b.4d.5h., 1p.2b.3b.4d.5h a.2e.3b. 4d.5h., 1b.2e.3b.4d.5h., 1f.2e.3b.4d.5h., 1h.2e.3b.4d.5h j.2e.3b.4d.5h., 1p.2e .3b.4d.5h., 1a.2f.3b.4d.5h. , 1 b.2f.3b.4d.5 f.2f.3b.4d.5h., 1h.2f.3b.4d.5h., 1j.2f.3b.4d.5h., 1p.2f.3b. 4d.5h a.2i.3b.4d.5h., 1b.2i.3b.4d.5h., 1f.2i.3b.4d.5h., 1h.2i.3b.4d.5h j.2i.3b .4d.5h., 1p.2i.3b.4d.5h., A.2m.3b.4d.5h., 1b.2m.3b.4d.5h. f.2m.3b.4d.5h., 1h.2m.3b.4d.5h., 1j.2m.3b.4d.5h., 1p.2m.3b.4d.5h. a.2o.3b.4d.5h., 1b.2o.3b.4d.5h., 1f.2o.3b.4d.5h., 1h.2o.3b.4d.5h. j.2o.3b.4d.5h., 1p.2o.3b.4d.5h., 1a.2u.3b.4d.5h., 1b.2u.3b.4d.5h. f.2u.3b.4d.5h., 1h.2u.3b.4d.5h., 1j.2u.3b.4d.5h., 1p.2u.3b.4d.5h. 1a.2y.3b.4d.5h., 1b.2y.3b.4d.5h., 1f.2y.3b.4d.5h., 1h.2y.3b.4d.5h. 1j.2y.3b.4d.5h., 1p.2y.3b.4d.5h., 1a.2a.3e.4d.5h., 1b.2a.3e.4d.5h. 1f.2a.3e.4d.5h., 1h.2a.3e.4d.5h., 1j.2a.3e.4d.5h., 1p.2a.3e.4d.5h. 1a.2b.3e.4d.5h., 1b.2b.3e.4d.5h., 1f.2b.3e.4d.5h., 1 h.2b.3e.4d.5h. 1j.2b.3e.4d.5h., 1p.2b.3e.4d.5h., 1a.2e.3e.4d.5h., 1b.2e.3e.4d.5h. 1f.2e.3e.4d.5h., 1h.2e.3e.4d.5h., 1j.2e.3e.4d.5h., 1 p.2e.3e.4d.5h la.2f.3e.4d .5h., 1b.2f.3e.4d.5h., 1f.2f.3e.4d.5h., 1h.2f.3e.4d.5h 1j.2f.3e.4d.5h., 1p.2f.3e.4d.5h., 1a.2i.3e.4d.5h., 1b.2i.3e.4d.5h 1f.2i.3e.4d.5h., 1h.2i.3e.4d.5h., 1j.2i.3e.4d.5h., 1 p.2i.3e.4d.5h. 1a.2m.3e.4d.5h., 1 b.2m.3e.4d.5h., 1f.2m.3e.4d.5h., 1 h.2m.3e.4d.5h. 1j.2m.3e.4d.5h., 1 p.2m.3e.4d.5h. , 1 a.2o.3e.4d.5h. , 1 b.2o.3e.4d.5h. 1f.2o.3e.4d: 5h., 1 h.2o.3e.4d.5h., 1 j.2o.3e.4d.5h., 1 p.2o.3e.4d.5h. 1a.2u.3e.4d.5h., 1 b.2u.3e.4d.5h., 1 f.2u.3e.4d.5h., 1 h.2u.3e.4d.5h. 1j.2u.3e.4d.5h., 1 p.2u.3e.4d.5h., 1 a.2y.3e.4d.5h. , 1 b.2y.3e.4d.5h. 1f.2y.3e.4d.5h., 1h.2y.3e.4d.5h., 1 j.2y.3e.4d.5h., 1 p.2y.3e.4d.5h. 1a.2a.3g.4d.5h., 1 b.2a.3g.4d.5h., 1 f.2a.3g.4d.5h. , 1 h.2a.3g74d.5h. 1j.2a.3g.4d.5h., 1 p.2a.3g.4d.5h., 1 a.2b.3g.4d.5h., 1 b.2b.3g.4d.5h. 1f.2b.3g.4d.5h., 1 h.2b.3g.4d.5h., 1 j.2b.3g.4d.5h., 1 p.2b.3g.4d.5h. 1a.2e.3g.4d.5h., 1b.2e.3g.4d.5h., 1 f.2e.3g.4d.5h. , 1 h.2e.3g.4d.5h. 1j.2e.3g.4d.5h., 1 p.2e.3g.4d.5h., 1 a.2f.3g.4d.5h., 1 b.2f.3g.4d.5h. 1f.2f.3g.4d.5h., 1 h.2f.3g.4d.5h., 1 j.2f.3g.4d.5h., 1 p.2f.3g.4d.5h. 1a.2i.3g.4d.5h., 1 b.2i.3g.4d.5h., 1 f.213g.4d.5h., 1 h.2i.3g.4d.5h. 1j.2i.3g.4d.5h., 1p.2i.3g.4d.5h., 1 a.2m.3g.4d.5h., 1 b.2m.3g.4d.5h. 1f.2m.3g.4d.5h., 1 h.2m.3g.4d.5h., 1 j.2m.3g.4d.5h., 1 p.2m.3g.4d.5h. 1a.2o.3g.4d.5h., 1 b.2o.3g.4d .5h. , 1f.2o.3g.4d.5h., 1 h.2o.3g.4d.5h. 1j.2o.3g.4d.5h., 1 p.2o.3g.4d.5h., 1 a.2u.3g.4d.5h., 1 b.2u.3g.4d.5h. 1f.2u.3g.4d.5h., 1h.2u.3g.4d.5h., 1 j.2u.3g.4d.5h., 1 p.2u.3g.4d.5h. 1a.2y.3g.4d.5h., 1 b.2y.3g.4d .5h. , 1 f.2y.3g.4d.5h., 1 h.2y.3g.4d.5h. 1j.2y.3g.4d.5h., 1 p.2y.3g.4d.5h., 1 a.2a.3a.4f.5h., 1 b.2a.3a.4f .5h. 1f.2a.3a.4f.5h., 1 h.2a.3a.4f.5h., 1 j.2a.3a.4f.5h., 1 p.2a.3a.4f .5h. 1a.2b.3a.4f.5h., 1 b.2b.3a.4f .5., 1f.2b.3a.4f.5., 1 h.2b.3a.4f .5h. 1j.2b.3a.4f.5h., 1 p.2b.3a.4f.5h., 1 a.2e.3a.4f.5h., 1 b.2e.3a.4f .5h. 1f.2e.3a.4f.5h., 1 h.2e.3a.4f .5h., 1 j.2e.3a.4f.5h., 1 p.2e.3a.4f .5h. 1a.2f.3a.4f.5h., 1b.2f.3a.4f.5h., 1f.2f.3a.4f.5h., 1h.2f.3a.4f.5. 1j.2f.3a.4f.5h., 1p.2f.3a.4f.5h., 1a.2i.3a.4f.5h., 1b.2i.3a.4f.5h. 1f.2i.3a.4f.5h., 1h.2i.3a.4f.5h., 1j.2i.3a.4f.5h., 1p.2i.3a.4f.5h. 1a.2m.3a.4f.5h., 1b.2m.3a.4f.5h., 1f.2m.3a.4f.5h., 1h.2m.3a.4f.5h. 1j.2m.3a.4f.5h., 1p.2m.3a.4f.5h., 1a.2o.3a.4f.5h., 1b.2o.3a.4f.5h. 1f.2o.3a.4f.5h., 1h.2o.3a.4f.5h., 1j.2o.3a.4f.5h., 1p.2o.3a.4f.5h. 1a.2u.3a.4f.5h., 1b.2u.3a.4f.5h., 1f.2u.3a.4f.5h., 1h.2u.3a.4f.5h. 1j.2u.3a.4f.5h., 1p.2u.3a.4f.5h., 1a.2y.3a.4f.5h., 1b.2y.3a.4f.5h. 1f.2y.3a.4f.5h., 1 h.2y.3a.4f.5h., 1j.2y.3a.4f.5h., 1p.2y.3a.4f.5h. 1a.2a.3b.4f.5h., 1b.2a.3b.4f.5h., 1f.2a.3b.4f.5h., 1h.2a.3b.4f.5h. 1j.2a.3b.4f.5h., 1p.2a.3b.4f.5h., 1a.2b.3b.4f.5h., 1b.2b.3b.4f.5h. 1f.2b.3b.4f.5., 1h.2b.3b.4f.5h., 1j.2b.3b.4f.5h., 1p.2b.3b.4f.5. 1a.2e.3b.4f.5h., 1b.2e.3b.4f.5., 1f.2e.3b.4f.5h., 1h.2e.3b.4f.5h. 1j.2e.3b.4f.5h., 1p.2e.3b.4f.5h., 1a.2f.3b.4f.5h., 1b.2f.3b.4f.5h. 1f.2f.3b.4f.5., 1h.2f.3b.4f.5h., 1j.2f.3b.4f.5h., 1p.2f.3b.4f.5h. 1a.2i.3b.4f.5h., 1b.2i.3b.4f.5h., 1f.2i.3b.4f.5h., 1h.2i.3b.4f.5h. 1j.2i.3b.4f.5h., 1p.2i.3b.4f.5h., 1a.2m.3b.4f.5h., 1b.2m.3b.4f.5h. 1f.2m.3b.4f.5h., 1h.2m.3b.4f.5., 1j.2m.3b.4f.5h., 1p.2m.3b.4f.5. 1a.2o.3b.4f.5h., 1b.2o.3b.4f.5h., 1f.2o.3b.4f.5h., 1h.2o.3b.4f.5h. 1j.2o.3b.4f.5h., 1p.2o.3b.4f.5h., 1a.2u.3b.4f.5h., 1b.2u.3b.4f.5h. 1f.2u.3b.4f.5h., 1h.2u.3b.4f.5., 1j.2u.3b.4f.5h., 1p.2u.3b.4f.5h 1a.2y.3b.4f.5h., 1b.2y.3b.4f.5h. , 1f.2y.3b.4f.5h. , 1h.2y.3b.4f.5 1j.2y.3b.4f.5h., 1p.2y.3b.4f.5h., 1a.2a.3e.4f.5h., 1b.2a.3e.4f.5h 1f.2a.3e.4f.5h., 1h.2a.3e.4f.5h., 1j.2a.3e.4f.5h., 1p.2a.3e.4f.5h 1a.2b.3e.4f.5h., 1b.2b.3e.4f.5h.,, 1f.2b.3e.4f.5h., 1h.2b.3e.4f.5h 1j.2b.3e.4f.5h., 1p.2b.3e.4f.5h., 1a.2e.3e.4f.5h., 1b.2e.3e.4f.5h. 1f.2e.3e.4f.5h., 1h.2e.3e.4f.5h., 1j.2e.3e.4f.5h., 1p.2e.3e.4f.5h. 1a.2f.3e.4f.5h., 1b.2f.3e.4f.5h., 1f.2f.3e.4f.5h., 1 h.2f.3e.4f.5h. 1j.2f.3e.4f.5h., 1p.2f.3e.4f.5h., 1a.2i.3e.4f.5h., 1b.2i.3e.4f.5. 1f.2i.3e.4f.5h., 1h.2i.3e.4f.5h., 1j.2i.3e.4f.5h., 1p.2i.3e.4f.5h. 1 a.2m.3e.4f.5., 1b.2m.3e.4f.5h., 1f.2m.3e.4f.5h., 1h.2m.3e.4f.5h. 1j.2m.3e.4f.5h., 1p.2m.3e.4f.5h., 1a.2o.3e.4f.5h., 1b.2o.3e.4f.5h. 1f.2o.3e.4f.5h., 1h.2o.3e.4f.5h., 1j.2o.3e.4f.5h., 1p.2o.3e.4f.5h. 1a.2u.3e.4f.5h., 1b.2u.3e.4f.5h., 1f.2u.3e.4f.5h., 1h.2u.3e.4f.5h. 1j.2u.3e.-4f.5h., 1p.2u.3e.4f.5h., 1a.2y.3e.4f.5h., 1b.2y.3e.4f.5. 1f.2y.3e.4f, 5., 1h.2y.3e.4f.5h., 1j.2y.3e.4f.5h., 1p.2y.3e.4f.5h. 1a.2a.3g.4f.5h., 1b.2a.3g.4f.5h., 1f.2a.3g.4f.5h., 1h.2a.3g.4f.5h. 1j.2a.3g.4f.5h., 1p.2a.3g.4f.5h., 1a.2b.3g.4f.5h., 1b.2b.3g.4f.5h. 1f.2b.3g.4f.5h., 1h.2b.3g.4f.5h., 1j.2b.3g.4f.5h., 1p.2b.3g.4f.5h. 1a.2e.3g.4f.5h., 1b.2e.3g.4f.5h., 1f.2e.3g.4f.5h., 1h.2e.3g.4f.5h. 1j.2e.3g.4f.5h., 1p.2e.3g.4f.5h., 1a.2f.3g.4f.5h., 1b.2f.3g.4f.5h. 1f.2f.3g.4f.5., 1h.2f.3g.4f.5., 1j.2f.3g.4f.5h., 1p.2f.3g.4f.5. 1a.2i.3g.4f.5h., 1b.2i.3g.4f.5h., 1f.2i.3g.4f.5., 1h.2i.3g.4f.5h. 1j.2i.3g.4f.5h., 1p.2i.3g.4f.5h., 1a.2m.3g.4f.5h., 1b.2m.3g.4f.5h. 1f.2m.3g.4f.5h., 1h.2m.3g.4f.5h., 1j.2m.3g.4f.5h., 1p.2m.3g.4f.5h. 1a.2o.3g.4f.5h., 1b.2o.3g.4f.5h., 1f.2o.3g.4f.5h., 1h.2o.3g.4f.5h. 1j.2o.3g.4f.5h., 1p.2o.3g.4f.5., 1a.2u.3g.4f.5h., 1b.2u.3g.4f.5h. 1f.2u.3g.4f.5h., 1h.2u.3g.4f.5h., 1j.2u.3g.4f.5h., 1p.2u.3g.4f.5h 1a.2y.3g.4f.5h., 1b.2y.3g.4f.5h. , 1f.2y.3g.4f.5., 1h.2y.3g.4f.5h 1j.2y.3g.4f.5h., 1p.2y.3g.4f.5h., 1 a.2a.3a.4g.5h., 1 b.2a.3a.4g.5 f.2a.3a.4g.5h., 1h.2a.3a.4g.5h 1j.2a.3a.4g.5. 1 p.2a.3a.4g.5. a.2b.3a.4g.5h., 1b.2b.3a.4g.5h. 1f.2b.3a.4g.5h. 1h.2b.3a.4g.5h. j.2b.3a.4g.5h., 1p.2b.3a.4g.5., 1a.2e.3a.4g.5h., 1b.2e.3a.4g.5h. f.2e.3a.4g.5h., 1h.2e.3a.4g.5h. 1j.2e.3a.4g.5h., 1p.2e.3a.4g.5h. a.2f.3a.4g.5h., 1b.2f.3a.4g.5h. 1f.2f.3a.4g.5h., 1h.2f.3a.4g.5h. j.2f.3a.4g.5h., 1p.2f.3a.4g.5h., 1 a.2i.3a.4g.5h., 1b.2i.3a.4g.5h. f.2i.3a.4g.5h., 1 h.2i.3a.4g.5h., 1j.2i.3a.4g.5h., 1p.2i.3a.4g.5h. a.2m.3a.4g.5h., 1 b.2m.3a.4g.5h 1f.2m.3a.4g.5h 1 h.2m.3a.4g.5. j.2m.3a.4g.5., 1 p.2m.3a.4g.5h. 1 a.2o.3a.4g.5., 1b.2o.3a.4g.5h. f.2o.3a.4g.5h., 1h.2o.3a.4g.5h. 1 j.2o.3a.4g.5h. 1p.2o.3a.4g.5h. a.2u.3a.4g.5h., 1b.2u.3a.4g.5h 1f.2u.3a.4g.5., 1h.2u.3a.4g.5h. j.2u.3a.4g.5., 1p.2u.3a.4g.5h., 1a.2y.3a.4g.5h., 1b.2y.3a.4g.5h. f.2y.3a.4g.5h., 1h.2y.3a.4g.5h. 1j.2y.3a.4g.5h. 1p.2y.3a.4g.5h. a.2a.3b.4g.5h., 1b.2a.3b.4g.5., 1f.2a.3b.4g.5h., 1h.2a.3b.4g.5h. j.2a.3b.4g.5h., 1p.2a.3b.4g.5h. 1a.2b.3b.4g.5h. 1b.2b.3b.4g.5h. f.2b.3b.4g.5h., 1h.2b.3b.4g.5h. 1j.2b.3b.4g.5h. 1p.2b.3b.4g.5h. a.2e.3b.4g.5h., 1b.2e.3b.4g.5h 1f.2e.3b.4g.5h. 1h.2e.3b.4g.5h. j.2e.3b.4g.5h., 1 p.2e.3b.4g.5., 1a.2f.3b.4g.5h. 1b.2f.3b.4g.5h. f.2f.3b.4g.5h., 1h.2f.3b.4g.5h. 1j.2f.3b.4g.5h. 1p.2f.3b.4g.5h. a.2i.3b.4g.5h., 1b.2i.3b.4g.5h. 1f.2i.3b.4g.5h. 1h.2i.3b.4g.5h. j.2i.3b.4g.5h., 1p.2i.3b.4g.5h., 1 a.2m.3b.4g.5h 1b.2m.3b.4g.5. f.2m.3b.4g.5., 1h.2m.3b.4g.5h. 1 j.2m.3b.4g.5., 1 p.2m.3b.4g.5h. a.2o.3b.4g.5h., 1b.2o.3b.4g.5h 1f.2o.3b.4g.5h 1h.2o.3b.4g.5h. j.2o.3b.4g.5h., 1p.2o.3b.4g.5h. 1a.2u.3b.4g.5h 1b.2u.3b.4g.5h f.2u.3b.4g.5h., 1h.2u.3b.4g.5h 1j.2u.3b.4g.5h. 1p.2u.3b.4g.5h a.2y.3b.4g.5h., 1b.2y.3b.4g.5h. 1f.2y.3b.4g.5h., 1 h.2y.3b.4g.5h. j.2y.3b.4g.5h., 1p.2y.3b.4g.5h., 1a.2a.3e.4g.5h., 1 b.2a.3e.4g.5h. f.2a.3e.4g.5h., 1h.2a.3e.4g.5h. 1j.2a.3e.4g.5h., 1 p.2a.3e .4g.5h. a.2b.3e.4g.5h., 1b.2b.3e.4g.5h. 1f.2b.3e.4g.5h., 1 h.2b.3e.4g.5h. j.2b.3e.4g.5h., 1p.2b.3e.4g.5h., 1a.2e.3e.4g.5h., 1 b.2e.3e.4g.5h. f.2e.3e.4g.5h., 1h.2e.3e.4g.5h. 1 j.2e.3e.4g.5., 1 p.2e.3e.4g.5h. a.2f.3e.4g.5., 1b.2f.3e.4g.5h., 1f.2f.3e.4g.5h., 1 h.2f.3e.4g.5h. j.2f.3e.4g.5h., 1p.2f.3e.4g.5h., 1a.2i.3e.4g.5h., 1 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j.2u.3e.4i.5i. 1 p.2u.3e.4i.5i. 1a.2y.3e.4i.5i. 1 b.2y.3e.4i.5i. f.2y.3e: 4i.5i. 1 h.2y.3e.4i.5i. 1 j.2y.3e.4i.5i. 1 p.2y.3e.4i.5i. a.2a.3g.4i.5i 1 b.2a.3g.4i.5i 1f.2a.3g.4i.5i. 1h.2a.3g.4i.5i. j.2a.3g.4i.5i. 1 p.2a.3g.4i.5i. 1a.2b.3g.4i.5i. 1b.2b.3g.4i.5i. f.2b.3g.4i.5i 1h.2b.3g.4i.5i 1j.2b.3g.4i.5i. 1p.2b.3g.4i.5i 1 a.2e.3g.4¡.5¡. 1b.2e.3g.4i.5i., 1f.2e.3g.4i.5i., 1 h.2e.3g.4i.5i., 1 j.2e.3g.4¡.5¡., 1p.2e.3g.4i.5i., 1a.2f.3g.4i.5i., 1 b.2f.3g.4i.5i., 1f.2f.3g.4i.5i., 1 h.2f.3g.4i.5i., 1j.2f.3g.4i.5i., 1 p.2f.3g.4i.5i., 1 a.2i.3g.4i.5¡., 1b.2i.3g.4i.5i., 1f.2i.3g.4i.5i., 1h.2i.3g.4i.5i., 1j.2i.3g.4i.5i., 1 p.2i.3g.4i.5i., 1 a.2m.3g.4i.5i., 1 b.2m.3g.4i.5i., 1 f.2m.3g.4i.5i. 1h.2m.3g.4i.5i., 1j.2m.3g.4i.5i., 1 p.2m.3g.4i.5i., 1 a.2o.3g.4i.5i. 1 b.2o.3g.4i.5i., 1f.2o.3g.4i.5i., 1 h.2o.3g.4i.5i., 1j.2o.3g.4i.5i., 1 p.2o.3g.4i.5i., 1 a.2u.3g.4i.5i., 1 b.2u.3g.4i.5i., 1 f.2u.3g.4i.5i., 1 h.2u.3g.4i.5i., 1j.2u.3g.4i.5i., 1 p.2u.3g.4i.5i., 1 a.2y.3g.4¡.5i. 1b.2y.3g.4i.5i., 1f.2y.3g.4i.5i., 1 h.2y.3g.4i.5i., 1j.2y.3g.4i.5i., And 1 p.2y.3g.4i.5i .. yet another embodiment, the compound of the present invention has an inhibitory activity against P450, at a level equal to or better than the activity inhibitor of a compound represented by an IC50 of less than about 2,000 nM, less than about 1,500 nM, less than about 1,000 nM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 650 nM , less than about 600 nM, less than about 550 nM, less than about 500 nM, less than about 400 nM, less than about 350 nM, less than about 300 nM, less than about 250 nM, less than about 200 nM, less of about 100 nM, or less than about 50 nM.
In still another embodiment, the compound of the present invention has an inhibitory activity against an isozyme of P450, for example, 3A, in a range represented by an IC50 of from about 2,000 nM to about 100 nM, from about 1,000 nM to about 100 nM , from about 900 nM to about 200 nM, from about 800 nM to about 300 nM, from about 700 nM to about 200 nM, from about 600 nM to about 200 nM, from about 500 nM to about 200 nM, of about 700 nM at about 300 nM, from about 600 nM to about 300 nM, from about 700 nM to about 400 nM, from about 600 nM to about 400 nM, from about 400 nM to about 100 nM, from about 300 nM to about 100 nM, or from about 600 nM to about 150 nM. In yet another embodiment, the compound of the present invention has an inhibitory activity against P450 at a level equal to or less than the inhibitory activity of a compound represented by an IC50 of less than about 2,000 nM, less than about 1,500 nM, less than about 1,000 nM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 650 nM, less than about 600 nM, less than about 550 nM, less than about 500 nM, less than about 400 nM, less than about 350 nM, less than about 300 nM, less than about 250 nM, less than about 200 nM, less than about 100 nM, or less than about 50 nM, provided that this compound also exhibits substantially no biological activities other than its inhibitory activity against P450. For example, the compound of the present invention may have a reduced or non-significant activity of protease inhibition, including, without limitation, a level of protease inhibition represented by an HIV EC50 greater than about 1,000 nM, greater than about 900 nM. , greater than about 800 nM, greater than about 700 nM, greater than about 600 nM, greater than about 500 nM, greater than about 400 nM, greater than about 300 nM, greater than about 200 nM, greater than about 100 nM, greater of about 50 nM, greater than about 40 nM, greater than about 30 nM, greater than about 20 nM, greater than about 10 nM, greater than about 5 nM, or greater than about 1 nM. In yet another embodiment, the compound of the present invention has an inhibitory activity specifically against one or more P450 isozymes, including, without limitation, 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2EI, and 3A4, 5, 7, etc.
In yet another embodiment, the compound of the present invention has an inhibitory activity specifically against an isozyme of P450, which is involved in the metabolization of anti-viral drugs, for example i ndinavir, nelfinavir, ritonavir, saquinavir etc. In yet another embodiment, the compound of the present invention has a specific inhibitory activity against one or more P450 isozymes, but not the others. For example, the compound of the present invention may have an inhibitor activity specifically against P450 3A, but a reduced, insubstantial, or minimal inhibitory activity against another isozyme of P450, for example P450 2C9. Pharmaceutical Formulations The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accordance with ordinary practice. The tablets will contain excipients, skimmers, fillers, agglutinants, and the like. The aqueous formulations are prepared in a sterile form, and when they are intended to be delivered by a different administration from the oral one, in general they will be isotonic. All formulations will optionally contain excipients, such as those stipulated in the Handbook of Pharmaceutical Excipients (1986), hereby incorporated by reference in its entirety. The excipients include ascorbic acid and other antioxidants, q uring agents such as EDTA, carbohydrates such as dextrin, hydroxy-alkyl-cellulose, hydroxy alkyl methyl cellulose, stearic acid, and the like. The pH of the formulations is in the range of about 3 to about 11, but ordinarily it is about 7 to 10. While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the invention, both for veterinary and human use, comprise at least one active Ingredient, for example, a compound of the present invention, together with one or more acceptable carriers, and optionally other therapeutic ingredients. The vehicles must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, and physiologically safe for the recipient thereof. The formulations include those suitable for the above administration routes. The formulations may conveniently be presented in a unit dosage form, and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations in general are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), Incorporated herein by reference in its entirety. These methods include the step of bringing the active ingredient into association with the vehicle, which constitutes one or more accessory ingredients. In general, the formulations are prepared by putting in association in a uniform and intimate way the active ingredient with liquid vehicles or finely divided solid vehicles, or both, and then, if necessary, the product is configured. The formulations of the present invention, suitable for oral administration, may be presented as separate units, such as capsules, lozenges, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as a liquid emulsion of oil in water, or as a liquid emulsion of water in oil. The active ingredient can also be administered as a bolus, electuary, or paste. A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compression, in a suitable machine, of the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder., lubricant, inert diluent, preservative, surface activity agent, or dispersing agent. The molded tablets can be made by molding, in a suitable machine, a mixture of the active ingredient powder moistened with an inert liquid diluent. The tablets may optionally be coated or scored, and optionally formulated to provide slow or controlled release of the ingredient. To be administered to the eyes or other external tissues, for example to the mouth and to the skin, the formulations are preferably apply as a topical ointment or cream containing the active ingredients in an amount, for example, from 0.075 to 20 weight percent / weight (including the active ingredients in a range of between 0.1 percent and 20 percent in increments of 0.1 percent weight / weight, such as 0.6 percent weight / weight, 0.7 percent weight / weight, etc.), preferably 0.2 to 1.5 percent weight / weight, and most preferably 0.5 to 10 percent weight / weight. When formulated in an ointment, the active ingredients may be employed with a paraffinic or water miscible base. In an alternative way, the active ingredients can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30 weight percent / weight of a polyhydric alcohol, that is, an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including P EG 400), and mixtures thereof. Topical formulations may desirably include a compound that improves the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of dermal penetration enhancers include dimethyl sulfoxide and related analogs. The oil phase of the emulsions of this invention may be constituted of known ingredients, of a known nature. Although the phase may comprise merely a n emulsifier (otherwise known as an emulsifier), desirably comprises a mixture of at least one emulsifier with a fat or an oil, or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifiers with or without stabilizers form the so-called emulsifying wax, and the wax together with the oil and the fat form the so-called emulsifying ointment base, which forms the dispersed oil phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate, and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining, and washable product, with a suitable consistency to prevent leakage from the tubes or other containers. Straight or branched mono- or di-basic alkyl esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, stearate, may be used. of butyl, 2-ethylhexyl palmitate, or a mixture of branched chain esters known as Crodamol CAP, with the latter three being preferred esters.
These can be used alone or in combination, depending on the required properties. Alternatively, high-melting lipids, such as white soft paraffin and / or liquid paraffin, or other mineral oils are used. The pharmaceutical formulations according to the present invention comprise one or more compounds of the invention, together with one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. The pharmaceutical formulations containing the active ingredient may be in any form suitable for the method of intended administration. When they are used for oral use, for example, tablets, troches, dragees, aqueous or oily suspensions, powders or dispersible granules can be prepared, emulsions, hard or soft capsules, syrups or Ixires. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and these compositions can contain one or more agents, including sweetening agents, flavoring agents, coloring agents, and preservatives, with the object of providing a pleasant reparation to the palate. Tablets containing the active ingredient mixed with a non-toxic pharmaceutically acceptable excipient, which is suitable for the manufacture of the tablets, are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin, or acacia; and lubricating agents, such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated by known techniques, including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax may be employed. Formulations for oral use may also be presented as hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules, where the active ingredient is mixed with water or with an oily medium, such as peanut oil, liquid paraffin, or olive oil. The aqueous suspensions of the invention contain the active materials mixed with excipients suitable for the manufacture of aqueous suspensions. These excipients include a suspending agent, such as sodium carboxy-methyl-cellulose, methyl-cellulose, hydroxy-propyl-methyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and acacia gum, and agents dispersants or humectants, such as naturally occurring phosphatide (e.g., litine), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with n a long-chain aliphatic alcohol (for example, hepta-deca-ethyleneoxy-cetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example, mono-oleate of polyoxyethylene sorbitan). The aqueous suspension may also contain one or more preservatives, such as ethyl or customary p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, and or no sweetening agents, such as sucrose or saccharin. Suspensions in oil can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as paraffin. Iquida Oral suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Adjuvant agents may be added, such as those stipulated herein, and flavoring agents, to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid. The d isperable powders and granules of the invention, suitable for the preparation of an aqueous suspension by the addition of water, provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing agents or humectants and suspending agents are exemplified by those disclosed above. There may also be additional excipients present, for example sweetening, flavoring, and coloring agents. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums, such as acacia gum and tragacanth gum, naturally occurring phosphatides., such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and the products of the condensation of these partial esters with ethylene oxide, such as mono - polyoxyethylene sorbitan oleate. The emulsion may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol, or sucrose. These formulations may also contain a demulcent, a preservative, a flavoring, or a coloring agent. The pharmaceutical compositions of the invention can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art, using suitable dispersing agents or humectants and suspending agents, which have been mentioned herein. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or it can be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed, including synthetic mono- or di-glycerides. In addition, in the same way fatty acids, such as oleic acid, can be used in the preparation of injectables. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a time release formulation intended for oral administration to humans may contain from about 1 to 1,000 milligrams of the active material combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95. percent of the compositions total (weight: weight). The pharmaceutical composition can be prepared to provide amounts that are easily measurable for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 micrograms of the active ingredient per milliliter of solution, so that the infusion of an adequate volume can be presented at a rate of approximately 30 milliliters. hour. Suitable formulations for administering to the eyes include eye drops, wherein the active ingredient is dissolved or suspended in a suitable vehicle, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in these formulations in a concentration of 0.5 to 20 percent, conveniently 0.5 to 10 percent, and in particular of about 1.5 percent in weight / weight. Formulations suitable for topical administration in the mouth include dragees comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pills comprising the active ingredient in an inert base, such as gelatin and giicerin, or sucrose and acacia; and mouth rinses comprising the active ingredient in an appropriate liquid vehicle. Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in increments of microwaves, as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passage or by inhalation through the mouth, to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for the administration of aerosol or dry powder can be prepared according to conventional methods, and can be supplied with other therapeutic agents, such as the compounds used hitherto in the treatment or profi laxis of infections. described in the present. Formulations suitable for vaginal administration can be presented as pessaries, buffers, creams, gels, pastes, foams, or aerosol formulations containing, in addition to the active ingredient, vehicles such as are known in the art as appropriate. Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions, which may contain anti-oxidants, pH regulators, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and Thickening agents. The formulations are presented in unit dose or multi-dose containers, for example sealed vials and flasks, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of the sterile liquid vehicle, for example. example water for injection, immediately before use. Solutions and suspensions for extemporaneous injection are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage forms are those containing a daily dose or a daily unit sub-dose, as mentioned hereinabove, or an ap ropy fraction thereof, of the active ingredient. It should be understood that, in addition to the ingredients provided by the present invention, the formulations of this invention may include other agents conventional in the art, having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The invention also provides veterinary compositions comprising at least one active ingredient, for example, a compound of the present invention, together with a veterinary vehicle. Veterinary vehicles are useful materials for the purpose of administering the composition, and may be materials solid, liquid, or gaseous, which are otherwise inert or acceptable in the veterinary art, and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route. The compounds of the invention can also be formulated to provide controlled release of the active ingredient, in order to allow less frequent dosing, or in order to improve the pharmacokinetic or toxicity profile of the active ingredient. In accordance with the above, the invention also provides compositions comprising one or more compounds of the invention, formulated for sustained or controlled release. The effective dose of the active ingredient depends at least on the nature of the condition being treated, on the toxicity, on whether the compound is being used prophylactically (lower doses) or against an active disease or condition, of the delivery method, and of the pharmaceutical formulation, and will be determined by the clinician using conventional dose scale studies. The effective dose can be expected to be from about 0.0001 to about 100 milligrams / - kilogram of body weight per day. Typically, from about 0.01 to about 10 milligrams / kilogram of body weight per day. More typically, from about 0.01 to about 5 milligrams / kilogram of body weight per day. More typically, of approximately 0.05 to approximately 0.5 milligrams / kilogram of body weight per day. For example, the daily candidate dose for an adult human being of ap- proximately 70 kilograms of body weight will be in the range of 1 mi ligramo to 1, 000 milligrams, or between 5 milligrams and 500 thousand igramos, and may take the form of a single dose or multiple doses. In still another embodiment, the present application provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and a pharmaceutically acceptable carrier or excipient. In still another embodiment, the present application provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable vehicle or excipient. According to the present invention, the therapeutic agent used in combination with the compound of the present invention can be any agent having a therapeutic effect when used in combination with the compound of the present invention. For example, the therapeutic agent used in combination with the compound of the present invention can be any agent that is accessible to the sensitive oxidative metabolism by the enzymes of cytochrome P450, especially the mono-oxygenase of the cytochrome P450. cytochrome P450, for example 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1, 3A4,5,7, etc. In another example, the therapeutic agent used in combination with the compound of the present invention can be any antiviral agent, for example anti-HIV, anti-HCV, etc., antibacterial agent, anti-fungal agent, immunomodulator, for example immunosuppressant, anti-neoplastic agent, chemotherapeutic agent, agents useful for the treatment of cardiovascular conditions, neurological conditions. etc. In yet another example, the therapeutic agent used in combination with the compound of the present invention can be any proton pump inhibitor, anti-epileptic agent, non-steroidal anti-inflammatory drug, oral hypoglycemic agent, angiotensin II, sulfonyl-ureas beta-blocker, antidepressant, anti-psychotic, or anesthetic, or a combination thereof. In still another example, the therapeutic agent used in combination with the compound of the present invention can be any of: 1) macrolide antibiotic, for example clarithromycin, erythromycin, telithromycin, 2) anti-arrhythmic, eg, quinidine->. 3-OH, 3) benzodiazepine, for example, alprazolam, diazepam? 30H, midazolam, triazolam, 4) immunomodulator, for example cyclosporin, tacrolimus (FK506), 5) HIV antivirals, for example indinavir, nelfinavir, ritonavir, saquinavir, 6) prokinetic, for example cisapride, 7) anti-histamine, for example astemizole, chlorpheniramine, terfenidine, 8) calcium channel blocker, example amlodipine, dlltiazem, felodlpina, lercanidipine, nisoldiplna, nitrendipine, verapamil, 9) inhibitors of HMG-CoA reductase, for example atorvastatin, cerivastatin, lovastatin, simvastatin, or 10) steroid 6beta-OH, eg estradiol, hydrocortisone, progesterone , testosterone. In yet another example, the therapeutic agent used in combination with the compound of the present invention can be any of alfentanil, aprepitant, aripiprazole, buspirone, cafergot, caffeine, TMU, cyclostazole, ***e, codeine-N-demethylation, dapsone, dextromethorphan, docetaxel, domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol, irinotecan, LAAM, lidocaine, methadone, nateglinide, ondansetron, pimozide, propranolol, quetiapine, quinine, salmeterol, sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine, zaleplon, or zolpidem, or a combination thereof. In one embodiment, the present application provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, in combination with at least one additional therapeutic agent selected from the group which consists of HIV protease inhibitor compounds, HIV reverse transcriptase inhibitors that are not nucleosides, HIV reverse transcriptase inhibitors that are nucleosides, HIV reverse transcriptase inhibitors that are nucleotides, HIV integrase inhibitors, inhibitors that do not they are HCV nucleotides, CCR5 inhibitors, and combinations thereof, and a pharmaceutically acceptable carrier or excipient. In another embodiment, the present application provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, in combination with at least one additional therapeutic agent selected from the group consisting of in amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649 , KNI-272, DPC-681, DPC-684, GW640385X, capravirin, emivirine, delaviridin, efavirenz, nevirapine, (+) calanolide A, etravirin, GW5634, DPC-083, DPC-961, DPC-963, MIV-150 , TMC-120, zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (± -FTC), D-d4FC, AVX754, tenofovir-disoproxil fumarate, adefovir, curcumin, curcumin derivatives, quicoric acid, quicoric acid derivatives, 3,5-dicafeoyl acid -quinolin, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic derivatives, phenethyl ester of caffeic acid, derivatives of phenethyl ester of caffeic acid, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, S -1360, zintevir (AR-177), L-870812, L-870810, benzimidazole derivatives, benzo-1, 2,4-thiadiazine derivatives / phenylalanine derivatives, aplaviroc, vicriviroc, and maraviroc, ciclosporin, FK-506 , rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186.318, LB71262, SC-52151 , SC-629 (N, N-dimethyl-glycyl-N- (2-hydroxy-3 - (((4-methoxy-phenyl) -sulfonyl) - (2-methyl-propyl) -arnino) -1- (phenyl) -rnethyl) -propyl) -3-methyl-L-varmarriida), K I-272, CGP 53437, CGP 57813 and U-103017, and a pharmaceutically acceptable carrier or excipient. In still another embodiment, the present application provides a combination pharmaceutical agent, which comprises: a) a first pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or ester thereof; and b) a second pharmaceutical composition, which comprises at least one additional therapeutic agent selected from the group consisting of HIV protease inhibitor compounds, non-nucleoside HIV reverse transcriptase inhibitors, HIV reverse transcriptase inhibitors that are nucleosides, HIV reverse transcriptase inhibitors that are nucleotides, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, alf inhibitors, glucosidase 1, hepatoprotectors, non-nucleoside HCV inhibitors, and other drugs for the treatment of HCV, and combinations thereof.
Routes of Administration One or more compounds of the invention (referred to herein as the active ingredients) are administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), and the like. It will be appreciated that the preferred route may vary, for example, with the condition of the receiver. An advantage of the compounds of this invention is that they are orally bioavailable, and can be dosed orally. Combination Therapy In one embodiment, the compounds of the present invention can be used alone, for example, to inhibit cytochrome P450 mono-oxygenase. In another embodiment, the compounds of the present invention are used in combination with other ingredients or active therapeutic agents. Preferably, the other ingredients or active therapeutic agents are metabolized or accessible for oxidative metabolism by cytochrome P450 enzymes, for example, mono-oxygenase enzymes, such as 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1, 3A4,5,7, etc. Combinations of the compounds of the present invention are typically selected based on the condition to be treated, the cross-activities of the ingredients, and the drug-properties of the combination. For example, when treats an infection (e.g., HIV or HCV), the compositions of the invention are combined with anti-infective agents (such as those described herein). In one embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more antiviral agents, for example anti-VlH, anti-HCV, etc., antibacterial agents, anti-fungal agents , immunomodulators, for example immunosuppressants, anti-neoplastic agents, chemo-therapeutic agents, agents useful for the treatment of cardiovascular conditions, neurological conditions, etc. In another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more proton pump inhibitors, anti-epileptics, non-steroidal anti-inflammatory drugs, oral hypoglycemic agents, angiotensin II, sulfonyl-ureas, beta blockers, antidepressants, anti-psychotics, or anesthetics, or a combination thereof. In yet another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more of: 1) macrolide antibiotics, eg, clarithromycin, erythromycin, telithromycin; 2) anti-arrhythmic, for example, quinidine? 3-OH, 3) benzodiazepine, for example, alprazolam, diazepam? 30H, midazolam, triazolam, 4) immunomodulator, for example cyclosporin, tacrolimus (FK506), 5) HIV antivirals, for example indinavir, nelfinavir, ritonavir, saquinavir, 6) prokinetic, for example cisapride, 7) anti-histamine, for example astemizole, chlorpheniramine, terfenidine, 8) calcium channel blocker, for example amlodipine, diltiazem, felodipine, lercanidipine, nisoldipine, nitrendipine, verapamil, 9) HMG-CoA reductase inhibitors, for example atorvastatin, cerivastatin, lovastatin, simvastatin, or 10) 6beta-steroid OH, for example estradiol, hydrocortisone, progesterone, testosterone. In still another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention, with one or more compounds selected from the group consisting of alfentanil, aprepitant, aripiprazole, buspirone, cafergot, caffeine, TU, ciclostazol, ***e, codeine-N-demethylation, dapsone, dextromethorphan, docetaxel, domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol, irinotecan, LAAM, lidocaine, methadone, nateglinide, ondansetron, pimozide, propanolol, quetiapine, quinine, salmeterol, sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine, zaleplon, or zolpidem, or a combination thereof. In still another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention, with one or more HIV protease inhibitor compounds, non-nucleoside reverse transcriptase inhibitors, transcriptase inhibitors. inverse of HIV which are nucleosides, inhibitors of HIV reverse transcriptase which are nucleotides, inhibitors of HIV integrase, inhibitors of gp41, inhibitors of CXCR4, inhibitors of gp120, inhibitors of CCR5, interferons, and other drugs for the treatment of HIV, interferons , ribavirin analogues, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, HCV inhibitors of nucleosides or nucleotides, non-nucleoside inhibitors of HCV, and other drugs for the treatment of HCV. More specifically, one or more compounds of the present invention can be combined with one or more compounds selected from the group consisting of: 1) amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir , brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, GS -8374, PPL-100, DG35, and AG 1859; 2) a non-nucleoside HIV reverse transcriptase inhibitor, for example capravirin, emivirine, delaviridin, efavirenz, nevirapine, (+) calanolide A, etravirin, GW5634, DPC-083, DPC-961, DPC-963, MIV- 150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806; 3) an HIV reverse transcriptase inhibitor which is nucleoside, for example zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, IV-210, Racivir (± -FTC), D-d4FC, emtricitabine, phosphazide, fozivudine-tidoxil, apricitribine (AVX754), GS-7340, KP-1461, and fosalvudine-tidoxil (formerly HDP 99,0003); 4) an HIV reverse transcriptase inhibitor which is nucleotide, for example tenofovir and adefovir; 5) an HIV integrase inhibitor, for example curcumin, curcumin derivatives, quicoric acid, quicoric acid derivatives, 3,5-dicaffeoyl-quinic acid, 3,5-dicaffeoyl-quinic acid derivatives, aurintricarboxylic acid, aurintricarboxílico, phenethyl-ester of caffeic acid, derivatives of phenethyl-ester of caffeic acid, tyrphostin, derivatives of tyrphostin, quercetin, quercetin derivatives, S-360, zintevir (AR-177), elvitegravir, L-870812, and L- 870810, MK-0518 (raltegravir), BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA 011; 6) a gp41 inhibitor, for example enfuvirtide, sifuvirtide, FB006M, and TRI-1144; 7) an inhibitor of CXCR4, for example AMD-070; 8) an entry inhibitor, for example SP01A; 9) a gp120 inhibitor, for example BMS-488043 or BlockAide / CR; 10) an inhibitor of G6PD and of NADH oxidase, for example, munitin; 11) a CCR5 inhibitor, for example aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004; 12) other drugs for the treatment of HIV, for example BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat ), Ampligen, HRG214, Cytolin, VGX-410, D-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 ( PA-040); 13) an interferon, for example pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rlFN-alpha 2b, rlFN-alpha 2a, IFN-alpha in consensus (infergen), feron, reaferon, intermax-alpha, r-IFN-beta, infergen + actinmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif , oral interferon-alpha, IFNalfa-2b XL, AVI-005, PEG-Infergen, and pegylated IFN-beta; 14) a ribavirin analogue, for example rebetol, copegus, viramidine (taribavirin); 15) a polymerase inhibitor NS5b, for example NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH -759, PF-868554, and GSK625433; 16) an NS3 protease inhibitor, for example SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191; 17) an alpha-glucosidase 1 inhibitor, for example MX-3253 (celgosivir), UT-231B; 18) hepatoprotectors, for example IDN-6556, ME 3738, LB-84451, and MitoQ; 19) a non-nucleoside HCV inhibitor, for example benzimidazole derivatives, benzo-1, 2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, GS-9190, and A-689; and 20) other drugs for the treatment of HCV, for example zadaxin, nitazoxanide (aligns), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, Gl -5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacine, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 ( merimepodib). It is also contemplated that compounds at room temperature can be used with any other agent or active therapeutic ingredient that is appreciably metabolized by cytochrome P450 mono-oxygenase enzymes, e.g. 3A mono-oxygenase of cytochrome P450, thereby reducing the amount or rate at which the other active therapeutic agent or ingredient is metabolized, whereby the pharmacokinetics of the other agent or active therapeutic ingredient is improved. These improvements may include elevating blood plasma levels of the other therapeutic agent or ingredient, or maintaining a more effective blood plasma level of the other active agent or therapeutic ingredient - compared to levels in the blood plasma of the other therapeutic agent or ingredient. Another agent or therapeutic ingredient administered without the compound of the present invention. It is also possible to combine any compound of the invention with one or more other active therapeutic agents, in a one-dose dosage form, for simultaneous or sequential administration to a patient. The combination therapy can be administered as a regimen whether multistep or in sequence. When administered sequentially, the combination can be administered in two or more administrations. The co-administration of a compound of the invention with one or more different active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, in such a way that Therapeutically effective amounts of the compound of the invention and of the one or more other active therapeutic agents in the patient's body are present. The co-administration includes the administration of dosages of the compounds of the invention before or after the administration of dosages of one or more different active therapeutic agents, for example the administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more different active therapeutic agents. For example, a unit dose of a compound of the invention, followed within seconds or minutes, may be administered first by the administration of a unit dose of one or more other active therapeutic agents. Alternatively, a dose of one or more different therapeutic agents may be administered first, followed by the administration of a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (for example, 1 to 12 hours), by the administration of a unit dose of one or more different active therapeutic agents . In other cases, it may be desirable to first administer a unit dose of one or more different active therapeutic agents, followed, after a period of hours (eg, 1 to 12 hours), by the administration of a unit dose of a compound of the invention. Combination therapy can provide "synergism" and a "nonsergic effect", that is, the effect achieved when the active ingredients used together is greater than the sum of the effects that result from using the compounds separately. A synergistic effect can be obtained when the active ingredients: (1) are co-formulated and administered or delivered simultaneously in a combined formulation; (2) are supplied alternating or in parallel, as separate formulations; or (3) through some other regime. When delivered in an alternating therapy, a synergistic effect can be obtained when the compounds are administered or delivered in sequence, for example, in tablets, pills, or separate capsules, or by different injections in separate syringes. In general, during the alternating therapy, an effective dosage of each active ingredient, i.e., in series, is administered sequentially, while in the combination therapy, effective dosages of two or more active ingredients are administered together. In still another embodiment, the present application provides a method for improving the pharmacokinetics of a drug that is metabolized by cytochrome P450 mono-oxygenase, which comprises administering to a patient treated with this drug, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. In yet another embodiment, the present application provides a method for improving the pharmacokinetics of a drug that is metabolized by cytochrome P450 mono-oxygenase, which comprises administering to a patient treated with this drug, a Therapeutically effective amount of a combination comprising this drug, and a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. In yet another embodiment, the present application proposes a method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 mono-oxygenase 3A, which comprises administering to a patient treated with this drug, an amount therapeutically effective of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. In still another embodiment, the present application provides a method for increasing blood plasma levels of a drug that is metabolized by cytochrome P450 mono-oxygenase, which comprises administering to a patient treated with this drug, an amount therapeutically effective of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. In still another modality, the present application proposes a method to increase the levels in the blood plasma of a drug that is metabolized by the cytochrome P450 mono-oxygenase, which comprises administering to a patient treated with this drug, a therapeutically effective amount of a combination comprising this drug and a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof.
In yet another embodiment, the present application provides a method for increasing blood plasma levels of a drug that is metabolized by cytochrome P450 mono-oxygenase 3A, which comprises administering to a patient treated with this drug, an amount Therapeutically effective of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. In yet another embodiment, the present application provides a method for increasing blood plasma levels of a drug that is metabolized by cytochrome P450 mono-oxy genase, which comprises administering to a patient treated with this drug, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and wherein the amount of the compound of the present invention administered is effective to inhibit cytochrome P450 mono-oxygenase. . In yet another modality, the present application provides a method for inhibiting cytochrome P450 mono-oxygenase in a patient, which comprises administering to a patient in need thereof, an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate , and / or ester thereof, effective to inhibit cytochrome P450 mono-oxygenase. In still another embodiment, the present application provides a method for inhibiting mono-oxygenase 3A of cytochrome P450 in a patient, which comprises administering to a patient who need, a quantity of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, effective to inhibit cyanochrome P450 mono-oxygenase 3A. In still another embodiment, the present application provides a method for inhibiting cytochrome P450 mono-oxygenase, which comprises contacting cytochrome P450 mono-oxygenase with an amount of a compound of the present invention, or a salt thereof. pharmaceutically acceptable, solvate, and / or ester of the same, effective to inhibit cytochrome P450 mono-oxygenase. In still another embodiment, the present application provides a method for inhibiting mono-oxygenase 3A of cytochrome P450, which comprises contacting cytochrome P450 mono-oxy genase 3A with an amount of a compound of the present invention. , or a pharmaceutically acceptable salt, solvate, and / or thereof, effective to inhibit the 3A mono-oxygenase of cytochrome P450. In still another embodiment, the present application provides a method for the treatment of a VI H infection, which comprises administering to a patient in need, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, transcriptase inhibitors i nverse of VI H which do not they are nucleosides, HIV reverse transcriptase inhibitors which are nucleosides, inhibitors of HIV reverse transcriptase which are nucleotides, inhibitors of HIV integrase, and inhibitors of CCR5. In still another embodiment, the present application provides a method for the treatment of an HIV infection, which comprises administering to a patient in need, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate , and / or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100 , DG35, AG 1859, capravirin, emivirine, delaviridin, efavirenz, nevirapine, (+) calanolide A, etravirin, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, T C-120, TMC-278 (rilpivireno), efavirenz, BILR 355 BS, VRX 840773, UK-453061, RDEA806, zidovu dina, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir (± -FTC), D-d4FC, emtricitabine, phosphazide, fozivudine-tidoxil, apricitibine (AVX754), amdoxovir, KP-146, fosalvudine-tidoxil (formerly HDP 99,0003), tenofovir, adefovir, curcumin, curcumin derivatives, quicoric acid, quicoric acid derivatives, 3,5-dicaphenoyl- quinoline, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, phenethyl ester of caffeic acid, phenethyl ester derivatives of caffeic acid, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, S -1360, zintevir (AR-177), L-870812, L-870810, MK-0518 (raltegravir), BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA 011, enfuvirtide, sifuvirtide, FB006M, and TRI-1144, AMD-070, an entry inhibitor, SP01A, BMS-488043, BlockAide / CR, an inhibitor of G6PD and NADH oxidase, immunitin, aplaviroc, vicriviroc, maraviroc, maraviroc, PRO-140, INCB15050, PF -232798 (Pfizer), CCR5mAb004, BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040). In still another embodiment, the present application provides a method for the treatment of an HCV infection, which comprises administering to a patient in need, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate , and / or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, IFN-alpha in consensus (infergen), feron, reaferon, intermax-alpha, r-IFN-beta, infergen + actinmune, IFN-omega with DUROS, locteron, albuferon, rebif, oral interferon-alpha, IFNalfa-2b XL, AVI-005, PEG-Infergen, and pegylated IFN-beta, rebetol, copegus, viramidine (taribavirin), NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, GSK625433, SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, ITMN-191, MX-3253 (celgosivir), UT-231B, IDN-6556, ME 3738, LB-84451, MitoQ, benzimidazole derivatives, benzo derivatives -1,2,4-thiadiazine, phenylalanine derivatives, A-831, A-689, zadaxin, nitazoxanide (aligns), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101) , KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvazin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab , Oglufanida, and VX-497 (merimepodib). In still another embodiment, the present application provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, for the preparation of a medicament for the inhibition of cytochrome mono-oxygenase. P450 in a patient. In yet another embodiment, the present application provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, for the preparation of a medicament for the treatment of an HIV infection. In yet another embodiment, the present application provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, for the preparation of a medicament for increasing levels in the blood plasma of the drug that is metabolized by cytochrome mono-oxygenase P450 In yet another embodiment, the present application provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, for the preparation of a medicament for improving the pharmacokinetics of a drug that is metabolized by mono-oxygenase of cytochrome P450. EXAMPLES Preparation of Example A Scheme 1 Example A Compound 2 To a solution of Compound 1 (ritonavir) (1.8 grams, 2.5 mmol) in 1,2-dichloro-ethane (15 milliliters), 1,1'-thiocarbonyl-di-imidazole (890 milligrams, 5.0 mmol) was added. ). The mixture was heated at 75 ° C for 6 hours, and cooled to 25 ° C. Evaporation under reduced pressure gave a white solid. Purification by flash column chromatography (stationary phase: silica gel; eluent: EtOAc) gave Compound 2 (1.6 grams), m / z 831.1 (M + H) +. Example AA the reflux solution of tributyl tin hydride (0.78 milliliters, 2.9 millimoles) in toluene (130 milliliters), a solution of Compound 2 (1.6 grams, 1.9 millimoles), and 2,2'-azobisisobutyronitrile ( 31 milligrams, 0.19 millimoles) in toluene (30 milliliters) for 30 minutes. The mixture was heated at 115 ° C for 6 hours, and cooled to 25 ° C. The toluene was removed under reduced pressure. Purification by flash column chromatography (stationary phase: silica gel, eluent: hexane / EtOAc = 1/10), gave Example 1 (560 milligrams), m / z: 705.2 (M + H) +. 1 H-NMR (CDCl 3) d 8.79 (1 H, s), 7.82 (1 H, s), 7.26-7.05 (10 H, m), 6.98 (1 H, s), 6.28 (1 H, m), 6.03 (1 H, m), 5.27 (1 H, m), 5.23 (2 H, s), 4.45-4.22 (2 H, m), 4.17 (1 H, m), 3.98 (1 H, m), 3.75 (1 H, m), 3.25 (1 H, m), 2.91 (3 H, s), 2.67 (4 H, m), 2.36 (1 H, m), 1.6-1.2 (10 H, m), 0.85 (6 H, m).
Preparation of Example B Scheme 2 Example B Example B To a solution of Compound 1 (ritonavir) (98 milligrams, 0.136 millimoles) in dichloromethane (4 milliliters) was added Dess-Martin periodinane (61 milligrams, 0.143 millimoles). The mixture was stirred at room temperature for 6 hours. Then it was partitioned between dichloromethane and brine, the dichloromethane layer was separated, dried, and evaporated to dryness. Purification with Combi-Flash® (stationary phase: silica gel; eluent: gradient of 40 to 80 percent EtOAc / hexane) gave Example B as a white solid. Example B was further purified by trituration with MeOH / hexane to give 83 milligrams of a white solid, m / z: 719 (M + H) +. Preparation of Example C Scheme 3 3. 4 I. Cyclopropyl amine, MeCN, room temperature Compound 3 Compound 3 was prepared according to the procedures of J. Med. Chem. 1998, 41, 602, incorporated herein by reference in its entirety for all purposes. Compound 4 A flask was charged with cyclopropyl-amine (8.2 milliliters, 117.8 mmol) at room temperature. A solution of Compound 3 (1 gram, 4.71 mmol) in MeCN (8.5 milliliters) was added dropwise over 5 minutes to produce a clear yellow solution, which was allowed to stand at room temperature overnight. The volatiles were removed in vacuo, and the resulting residue was purified by silica gel chromatography (gradient elution, 0 to 50 percent EtOAc / hexane), to give 0.65 grams (70 percent) of 4 as a liquid yellow (LC / MS m / z 197 (M + H) +; 218 (M + Na) +). Scheme 4 II. Ambient temperature, DCM; III. 1M LiOH, THF / H20. Compound 5 Compound 5 was purchased from Aldrich, or was prepared in an alternative manner according to the procedures of J. Orq. Che. 1994, 59, 1937, incorporated herein by reference in its totality for all purposes. Compound 6 To a solution of Compound 4 in dichloromethane (3 milliliters) at room temperature was added 5 (0.1 milliliter, 0.695 mmol). The resulting clear solution was allowed to stand at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was passed through chromatography directly, using silica gel chromatography (gradient elution, 0 to 50 percent EtOAc / hexane), to yield 0.218 grams (89 percent) of the solvent. (LC / MS m / z 354 (M + H) +; 729 (2M + Na) +) as a colorless crystal.
Compound 7 Compound 6 was taken up in tetrahydrofuran (5 milliliters) at room temperature, and LiOH (1M in H20) was added. Then the resulting reaction mixture was stirred vigorously for 1.5 hours. The reaction mixture was acidified with 1 M HCl to a pH of 3 (monitored using pH test strips). Then the acidified reaction mixture was extracted several times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4, and concentrated in vacuo to yield 0.20 grams (quantitative yield) of 7 (LC / MS m / z 340 (M + H) 4") as a colorless film. This material was used without further purification.
Scheme 5 Example C Compounds 7 (0.034 grams, 0.100 millimoles) and 8 (0.034 grams, 0.083 millimoles) were diluted in tetrahydrofuran (2 milliliters) at room temperature. To the resulting solution were added N, N-di-isopropyl-ethyl-amine (0.022 milliliters, 0.125 millimoles), EDC (0.018 milliliters, 0.099 millimoles), and HOBt (0.013 grams, 0.099 millimoles). Then the solution was allowed to stand overnight at room temperature. The solvent was removed in vacuo, and the residue was taken up in MeCN (0.5 milliliters), and passed through an Acrodisc LC13 PVDF filter (0.45 microns) before purification by HPLC preparation, to provide 0.043 grams (71 percent) of Example C as a fluffy white solid. (1 H-NMR (300 MHz, CDCl 3) d 8.79 (s, 1H), 7.82 (s, 1H), 7.27-7.02 (m, 10 H), 6.81 (s, 1H), 5.97 (br d, J = 8.7 Hz, 1H), 5.76 (br d, J = 7.2 Hz, 1H), 5.21 (dt, J = 7.5, 12.6 Hz72H), 5.02, br d, J = 8.4 Hz, 1H); 4.58 (s, 2H); 4.16 (m, 1H); 3.99 (br t, J = 6.6 Hz, 1H); 3.79 (m, 1H); 3.27 (pent, J = 6.6 Hz, 1H); 2.85-2.50 (m, 3H); 2.23 (m, 1H); 1.82 (br s, 2H); 1.60-1.22 (m, 4H); 1.36 (d, J = 6.6 Hz, 6H); 0.91 (d, J = 6.6 Hz, 3H); 0.90-0.7 (m, 4H); 0.80 (d, J = 6.6 Hz, 3H); LC / MS m / z 731 (M +)).
Preparation of Examples D-l Esauema 6 I. Et3N / DMAP / THF / 65 ° C; II. CH2CI2 / 25 ° C; a: R = H d: R = CH2OBn III. to. NaOH / dioxane / H20; b. HCI. b: R = CH 2 e: R = CH (0-t-Bu) CH 3 c: R = CH 2 CH 3 f: R = CH (OH) CH 3 Compound 9 Compound 9 was prepared according to the procedures of J. Med. Chem 1998, 41, 602. Compound 10 The structures of Compound 10 were prepared according to the procedures of J. Med. Chem. 1998, 41, 602. Compound 11 The structures of Compound 11 were purchased from Aldrich, or were prepared in accordance with procedures of J. Med. Chem. 1994, 59, 1937. Compound 12 Method 1: To a solution of Compound 9 (0.8 mmol) in tetrahydrofuran (2 milliliters), a carbamate of Compound 10 (0.6 mmol) was added, followed by DMAP (16 milligrams) and triethylamine (0.25 milliliters). The resulting mixture was heated at 70 ° C for 2 hours, and diluted with EtOAc. The organic phase was separated and washed in sequence with saturated aqueous Na 2 SO 4, water, and brine, and then concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, gradient of 1/1 - 1/3 hexanes / EtOAc) gave the compounds of Structure 12. Method 2: To a solution of the Compound (2.4 mmol) in CH 2 Cl 2 (2 milliliters) an isocyanate of Compound 11 (2 mmol) was added. The resulting mixture was stirred for 4 hours, and concentrated. Purification of the residue by flash column chromatography (silica gel, hexane / EtOAc, 1/1 - 1/3) gave the structures of Compound 12. Compound 13 To a solution of the structures of Compound 12 (1.2 mmol) in dioxane (8 milliliters) and water (8 milliliters), sodium hydroxide (3.6 millimoles) was added. The resulting reaction mixture was stirred for 1 hour, and acidified with HCl in dioxane (3.6 mmol). The reaction mixture was extracted with EtOAc, and the organic phase was dried with anhydrous MgSO 4. The concentration of the dry organic phase gave the structures of Compound 13. Scheme 14 13 16 t. Et9N / DCM Compound 16 To a solution of Compound 15 (obtained commercially in Molekula) (17 mmol) in dichloromethane (40 milliliters), Compound 14 (19 mmol) was added, followed by triethylamine (26 mmol). The resulting reaction mixture was stirred for 12 hours, and concentrated under reduced pressure. The reaction mixture was diluted with EtOAc, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (silica gel, eluent: hexanes / EtOAc = 1/1) gave Compound 16 (4.7 grams). Scheme 8 Examples: D: R = H.
E: R = CH3. F: R = C H 2 C H 3. G: R = CH 2 O B n. H: R = CH (0-t-Bu) CH 3 1: R = CH (OH) CH 3. I. a. n-BuLi / -78 ° C; b. i-Bu2AI (OMe); II. to. Ac20 / pyridine; b. Na-Hg / eOH / THF; III. Na / NH3 / -33 ° C; IV. to. H20 / Pd / C at 10 percent; b. TFA / DCM; V. 16 / Et3N; SAW. to. acid of structure 13 / EDC / HOBt. Compound 17 Compound 17 was prepared according to the procedures of Tetrahedron 1997, 53, 4769, incorporated herein by reference in its entirety for all purposes. Compound 18 Compound 17 was prepared according to the procedures of J. Ora. Chem. 1987, 52, 3759, incorporated herein by reference in its entirety for all purposes. Compound 19 A suspension of Compound 18 (7.4 mmol) in tetrahydrofuran (200 milliliters) was heated under reflux until a clear solution was obtained. The solution was cooled to -78 ° C, and n-butyllithium (14.8 mmol) was added dropwise, to give a solution of the sulfone dianion 18. To a solution of DIBAL-H (7.8 mmol) at 0 ° C, a solution of MeOH (7.8 mmol) in tetrahydrofuran (5 milliliters) was added. The mixture was stirred for 5 minutes, and cooled to -78 ° C.
A solution of Compound 17 (6.6 mmol) in tetrahydrofuran (5 milliliters) was added to the above solution of DIBAL-H / MeOH, and the resulting reaction mixture was stirred for another 5 minutes. The resulting solution of the aldehyde complexes was transferred to a solution of the sulfone dianion 18. The resulting mixture was stirred at -78 ° C for 30 minutes, quenched with an aqueous solution of NH 4 Cl, and heated to 25 ° C. . The mixture was then extracted with EtOAc, and concentrated, to give Compound 19 as a mixture of diastereomers. (m / z 737.3 (M + Na) +). Example 20 To a solution of Compound 19 in dichloromethane (20 milliliters), Ac20 (1.5 milliliters) was added, followed by pyridine (3 milliliters). The resulting mixture was stirred for 12 hours and concentrated. The concentrate was dissolved in MeOH (30 milliliters), and cooled to 0 ° C. To the solution was added NaH2P04 (4.9 grams), followed by freshly prepared Na-Hg (at 6 percent, 6 grams). The resulting mixture was heated to 25 ° C, and stirred for 12 hours. Then water (50 milliliters) was added, and the mixture was filtered and concentrated. The concentrate was diluted with EtOAc, and washed with brine. The organic phase was concentrated. Purification by flash column chromatography (silica gel, eluent: hexanes / EtOAc = 10/1), gave Compound 20 (1.4 grams). Compound 21 To liquid ammonia (25 milliliters) at -33 ° C, a solution of Compound 20 (1.4 grams) in tetrahydrofuran 82.5 was added. milliliters). Sodium was slowly added until the blue color of the solution persisted. The resulting mixture was stirred for 1 hour. Solid NH4CI (6 grams) was then added slowly, the mixture was heated to 25 ° C, and the ammonia was evaporated. The mixture was diluted in EtOAc, and washed sequentially with water and brine. The solvent was removed under reduced pressure. Purification of the resulting residue by flash column chromatography (silica gel, eluent: hexanes / EtOAc = 5/1) gave Compound 21 (1.15 grams). Compound 22 A mixture of Compound 21 (1.15 grams) and 10 percent Pd / C (160 milligrams) in MeOH (20 milliliters) was hydrogenated for 12 hours. Celite was added, and the resulting mixture was stirred for 5 minutes. Then the mixture was filtered and concentrated to give an intermediate (1 gram). The intermediate (700 milligrams) was dissolved in dichloromethane (20 milliliters) and trifluoroacetic acid (4 milliliters), and the resulting mixture was stirred for 4 hours, and then concentrated under reduced pressure. The concentrated mixture was diluted with EtOAc, and washed in sequence with saturated aqueous Na 2 CO 3, water, and brine. Concentration of the washed EtOAc mixture gave Compound 22 (420 milligrams). Compound 8 To a solution of Compound 22 (1.57 mmol) in CH 3 CN (16 milliliters) was added Compound 16 (1.57 mmol), followed by di-isopropyl-ethyl-amine (3.14 mmol). The resulting mixture is stirred for 12 hours. The mixture was then diluted with EtOAc, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. Purification by reverse phase HPLC (Phenomenex Synergi®, Comb-HTS column, eluent: 25 to 100 percent CH3CN in water) gave Compound 8 (460 milligrams). Example DA the solution of Compound 13a (R = H, 0.08 mmol) and Compound 8 (0.06 mmol) in tetrahydrofuran (1 milliliter), were added HOBt (15 milligrams), EDC (26 milligrams), and di-isop ropil -ethyl-amine (0.25 milliliters). The mixture was stirred for 12 hours, and concentrated. Purification by reverse phase HPLC (Phenomenex Synergi®, Comb-HTS column, eluent: 25 to 100 percent CH3CN in water) gave Example D (27 milligrams), m / z 663.1 (M + H) +. 1 H-NMR (CDCl 3) d 8.79 (1 H, s), 7.83 (1 H, s), 7.25-7.04 (10 H, m), 6.98 (1 H, s), 6.25 (1 H, m), 5.25 (3 H, m), 4.40 (2 H, s), 4.12 (1 H, m), 3.8 (3 H, m), 3.22 (1 H, m), 2.95 (3 H, s), 2.70 (4 H , m), 1.60 (4 H, m), 1.26 (6 H, d, J = 7 Hz). Example E Example E was prepared following the procedure for Example D (30 milligrams), except that Compound 13b was used in place of Compound 13a. m / z 677.1 (M + H) +. Example F Compound F was prepared following the procedure for Example D (40 milligrams), except that Compound 13c was used in place of Compound 13a. m / z 691.2 (M + H) +. 1 H-NMR (CDCl 3) d 8. 80 (1 H, s), 7.83 (1 H, s), 7.25-7.06 (10 H, m), 6.98 (1 H, s), 6.35 (1 H, m), 6.23 (1 H, m), 5.24 (2 H, s), 5.12 (1 H, m), 4.34 (2 H, s), 4.10 (2 H, m); 3.78 (1 H, m), 3.23 (1 H, m), 2.90 (3 H, s), 2.68 (4 H, m), I.90 (2 H, m), 1.7-1.4 (4 H, m), 1.36 (6 H, d, J = 7.0 Hz), 0.90 (3 H, t, J = 7.3 Hz). Example G Example G was prepared following the procedure for Example D (84 milligrams), except that Compound 13d was used in place of Compound 13a. m / z 783.2 (M + H) +. Example H Example H was prepared following the procedure for Example D (90 milligrams), except that Compound 13e was used in place of Compound 13a. m / z 763.2 (M + H) +. Example I Example H (24 milligrams) was dissolved in trifluoroacetic acid (2 milliliters), and the mixture was stirred for 12 hours, and then concentrated. Purification by reverse phase HPLC (Phenomenex Synergi®, Comb-HTS column, eluent: 25 to 100 percent CH3CN in water) gave Example I (14 milligrams), m / z 707.2 (M + H) +. 1 H-RN (CDCl 3) d 8.82 (1 H, s), 7.85 (1 H, s), 7.26-7.04 (10 H, m), 7.0 (1 H, s), 5.25 (2 H, s), 4.86 (1 H, m), 4.56 (1 H, m), 4.37 (2 H, m), 4.13 (1 H, m), 4.06 (1 H, m), 3.86 (1 H, m), 3.32 (1 H, m), 2.99 (3 H, s), 2.8-2.6 (4 H, m), 1.6-1.4 (4 H, m), 1.37 (6 H, m), I.15 (3 H, m).
Preparation of Example J Scheme 9 Example J I. EDC / HOBt Example J Compound 23 was prepared following the procedure for Compound 13, with the exception that methyl 3-isocyanatopropionate was used in place of Compound 11. Example J was prepared following the procedure for Example D (37 milligrams), except that Compound 23 was used in place of Compound 13a. m / z 677.2 (M + H) +. Preparation of Example K Scheme 10 I. NaN3 / DMF; II. PPh3 / H20; III. to. CI3COCOOCCI3; b. HCl- NH2CH, PrC02Et; IV. to. NaOH; b. HCI; V. EDC / HOBt / Compound 8. Example K Compound 5a Compound 5a was prepared following the procedure of the Synthesis literature 823, 1976, incorporated herein by reference in its entirety for all purposes. Compound 5b To the solution of Compound 5a (700 milligrams, 3.9 mmol) in tetrahydrofuran (10 milliliters) was added water (69 microliters, 3.9 mmol), followed by triphenylphosphine (1.06 grams, 4.0 mmol). The mixture was stirred for 12 hours. The solvents were removed, and the mixture was dried to give Compound 5b, which was used for the next step without further purification. Compound 5c To a solution of triphosgene (110 milligrams, 0.37 millimoles) in CH 2 Cl 2 (2 milliliters) at 0 ° C, was added a solution of Compound 5b (1 millimole) in iPrNEt 2 (0.38 milliliters, 2.2 millimoles) in CH 2 Cl 2 (3.5 milliliters) for a period of 30 minutes. The mixture was stirred for 30 minutes, and a solution of the HCl salt of the amino-N-methyl-leucine methyl ester (182 milligrams, 1 millimole), and iPrNEt2 (0.34 milliliters, 2.2 millimoles) in CH2Cl2 ( 2 milliliters). The mixture was stirred for 12 hours, and diluted with EtOAc. The solution was washed with saturated Na 2 CO 3 (twice), water (twice), and brine, and dried over Na 2 SO 4. The concentration and purification by flash chromatography on silica gel gave Compound 5c (300 milligrams). Compound 5d Compound 5d was prepared following the procedure for Compound 13, with the exception that Compound 5c was used in place of Compound 12. Example K Example K was prepared following the procedure for Example D (7 milligrams), except that Compound 5d was used in place of Compound 13a. m / z 705.2 (M + H) +. 1 H-NMR (CDCl 3) d 8.8 (1 H, m), 7.86 (1 H, s), 7.26-6.8 (11 H, m), 6.10 (1 H, m), 5.5-5.10 (4 H, m) , 4.46 (2 H, m), 4.2-3.75 (3 H, m), 3.25 (1 H, m), 2.82 / 2.4 (3 H), 2.8-2.5 (4 H, m), 2.17 (1 H, m), 1.7-1.2 (10 H7 m), 0.8 (6 H, m). Preparation of Example L Scheme 11 Example L I. Et3N Example L To a solution of Compound 22 (1.57 mmol) in CH3CN (16 milliliters), Compound 16 (3.14 millimoles) was added, followed by triethylamine (4.71 millimoles). The resulting mixture was stirred for 12 hours. The reaction mixture was diluted with EtOAc, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (silica gel, eluent: hexanes / EtOAc = 1/1) gave Example L (460 milligrams), m / z 551.2 (M + H) +. 1 H-NMR (CDCl 3) d 8.81 (2 H, s), 7.85 (2 H, s), 7.26-7.0 (10 H, m), 5.24 (4 H, s), 4.50 (2 H, m), 3.87 (2 H, m), 2.73 (4 H, m), 1.4-1.2 (4 H, m). Alternative Preparation of Compound 22 Scheme 12 I. TCDI / THF / 65 ° C; II. P (OEt) 3/60 ° C; III. 10% Pd / C / i-PrOH / EtOAc.
Compound 25 Compound 25 was prepared following the procedure of the literature described in J. Ora. Chem. 1996, 61, 444 (incorporated herein by reference in its entirety), except that the L-isomer was prepared in place of the D-isomer.
Compound 26 A mixture of Compound 25 (7.4 grams) and 1,1'-thiocarbonyl-di-imidazole (4.5 grams) in tetrahydrofuran (260 milliliters) was heated at 65 ° C for 54 hours. The solvent was removed from the mixture under reduced pressure. Purification by flash chromatography (silica gel, hexanes / EtOAc = 1/1) gave Compound 26 (7.33 grams). Compound 27 The mixture of Compound 26 (7.3 grams) and triethyl phosphite (100 milliliters) was heated at 160 ° C for 4 hours. The excess reagent was removed under reduced pressure. Purification by flash column chromatography (silica gel, hexanes / EtOAc = 3/1) gave Compound 27 (5 grams). Compound 22 A mixture of Compound 27 (250 milligrams) in i-PrOH / EOAc (5 milliliters / 5 milliliters) was hydrogenated for 14 hours in the presence of 10 percent Pd / C (75 milligrams). Celite was added to the mixture, and the mixture was stirred for 5 minutes. Filtration and evaporation of the solvents gave Compound 22 (116 milligrams). The skilled practitioner will recognize that the method illustrated in Scheme 12 can be used to prepare a variety of 1,4-substituted 1,4-diamines analogous to Compound 22. For example, a 2,3-dihydroxy-1 can be prepared, 4-diamine protected by amine analogous to Compound 25: Analogs of Compound 25 wherein L3, A, Ar, and P are as defined herein, and the "P" protecting group is any amine protecting group described in Protective Groups in Orqanic Svnthesis, Theodora W. Greene and Peter GM Wuts (John Wiley &Sons, Inc., New York, 1999, ISBN 0-471-16019-9), which is incorporated herein by reference in its entirety for all purposes. Then the analogs of Compound 25 can be transformed, according to the methods illustrated in Scheme 12, to form analogs of Compound 26: Analogs of Compound 26; Analogs of Compound 27: Analogs of Compound 27; Y Analogs of Compound 22: Analogs of Compound 22. Preparation of Examples M and N Scheme 13 I. a. LiOH, THF / H20, 25 ° C; b. HCI. Compound 29 Compound 28 was prepared using a procedure similar to that used to prepare Compound 6 (described in Scheme 4), except that Compound 9 was used in place of Compound 4. To a solution of Compound 28 (757 grams, 2.31 millimoles) in tetrahydrofuran (9 milliliters) at room temperature, freshly prepared 1M LiOH (4.6 milliliters, 4.6 millimoles) was added. After 1.5 hours, 1 M HCl (7 milliliters, 7 mmol) was added, and the reaction mixture was completely extracted with EtOAc (15 milliliters, five times). The combined organic layers were dried over anhydrous Na2SO4, and the volatiles were removed in vacuo, to provide 0.677 grams (93 percent) of Compound 29 as a solid colorless glaze (LC / MS m / z 314.0 (M + H) +) which was used in the following procedures without further purification. Scheme 14 Ph - "Ph BocHN HBOC J3L H? N ^ NH2.2TFA 37 38 I. a. PhCHO, MeOH; b. NaBH4; c. Boc20, THF / HzO, II. Pyr »S03, Et3, DMSO 0 ° C, III. n-BuLi, MeOAI (i-Bu) 2, THF, -78 ° C. IV. to. Ac20, pyr, CH2Cl2, b.6% Na / Hg, Na2HP04, MeOH. V. H2l Pd / C at 10 percent, MeOH. SAW. Na / NH3 > THF, -35 ° C, VII.20% TFA / DCM. Compound 30 Compound 30 was purchased from Aldrich Chemical Co., and used without further purification. Compound 31 To a solution of Compound 30 (8.25 grams, 80 mmol) in MeOH (50 milliliters), benzaldehyde (8.1 milliliters, 80 mmol) was added, and the resulting solution was allowed to stir at room temperature. ambient. After 2 hours, the reaction mixture was cooled to 0 ° C, and NaBH 4 (3.33 grams, 88 mmol) was added in portions. After allowing the reaction mixture to warm to room temperature for 2 hours, glacial acetic acid (2 milliliters) was added. The resulting viscous solution was concentrated in vacuo. EtAOc and H20 (50 milliliters each) were added, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated NaHCO 3, brine, and concentrated in vacuo. The resulting material was absorbed in tetrahydrofuran (25 milliliters) and H20 (25 milliliters) at room temperature, and Boc20 (15.1 grams, "69.2 mmol) was added to produce an opaque suspension, which was stirred vigorously for 2 hours at room temperature. The tetrahydrofuran was removed in vacuo, and the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine, dried over anhydrous MgSO 4, and concentrated in vacuo. hexanes / EtOAc) afforded 18.5 grams (79 percent) of Compound 31 as a colorless oil (LC / MS m / z 293.9 (M + H) +) Compound 32 Compound 31 (5.95 grams, 20.3 mmol) and Et3N ( 9.9 milliliters, 71 mmol) was diluted in dimethyl sulfoxide (65 milliliters), and allowed to age at room temperature for 30 minutes, before cooling to 0 ° C. "S03" pyridine was added in one portion, and the reaction mixture was added. kept at 5 ° C to prevent freezing n. After 45 minutes, the reaction mixture was poured in ice water, and extracted with EtAOc. The combined organic layers were washed with saturated NaHCO3, H20, and dried over anhydrous MgSO4 before concentration in vacuo (bath temperature of 25 ° C), to yield 4.39 grams (74 percent) of Compound 32, as a color oil transparent yellow, which was used without further purification. 1 H-NMR (CDCl 3, 300 MHz) d (major rotamer) 9.36 (br s, 1H); 5.01 (d, J = 15 Hz, 1H); 4.12 (d, J = 15 Hz, 1H); 3.45 (m, 1H); 2.04-1.88 (m, 1H); 1.80-1.58 (m, 1H); 1.54-1.20 (m, 2H); 1.47 (s, 9H); 0.91 (t, J = 7.2 Hz, 3H). (minor rotamer) 9.46 (br s, 1H); 4.71 (d, J = 15 Hz, 1H); 4.20 (d, J = 15 Hz, 1H); 3.78 (m, 1H); 2.04-1.88 (m, 1H); 1.80-1.58 (m, 1H); 1.54-1.20 (m, 2H); 1.47 (s, 9H); 0.91 (t, J = 7.2 Hz, 3H). Compound 34 A suspension of Compound 33 (6.23 grams, 16.6 mmol) in tetrahydrofuran (500 milliliters) was heated under reflux, until a homogeneous solution was obtained. The solution was cooled to -78 ° C, and N-BuLi 1.6M (19.7 milliliters, 31.5 mmol) was introduced to produce a clear yellow solution. Meanwhile, DIBAL-OMe was prepared by diluting the DIBAL-H (1M in hexanes, 18.1 milliliters, 18.1 millimoles) in tetrahydrofuran (8 milliliters), and cooling to 0 ° C before the addition of MeOH (0.73 milliliters, 18.1 millimoles). This solution was allowed to age, while Compound 32 (4.39 grams, 15.1 mmol) was diluted in tetrahydrofuran (15 milliliters), and cooled to -78 ° C. The DIBAL-OMe solution was cannulated to the solution of Compound 32, and left aging for 5 minutes before cannulation to the solution of the sulfur dianion. The resulting clear yellow solution was allowed to age at -78 ° C for 1 hour. The reaction was quenched by the addition of saturated NH 4 Cl (100 milliliters) at -78 ° C, and allowed to warm to room temperature. Water was added until all the precipitated solids dissolved, and the layers were separated. The tetrahydrofuran layer was concentrated in vacuo, while the aqueous layer was extracted with EtOAc. The recombined organic layers were washed with brine, and the resulting emulsion was treated with solid NaOH until homogenous bilayers were formed. The aqueous layer was extracted with EtOAc, and the combined organics were dried over anhydrous Na2SO4. Concentration in vacuo afforded 9.57 grams (95 percent) of Compound 34 as an amorphous white solid (LC / MS m / z: 689.3 (M + Na) +), which was used in the following procedures without further purification. Compound 35 Crude Compound 34 was suspended in CH 2 Cl 2 (65 milliliters), followed by the addition of pyridine (6.7 milliliters, 83 mmol) and acetic anhydride (3.5 milliliters, 36.5 mmol). The resulting solution was allowed to age at room temperature overnight. MeOH (6 milliliters) was added, and, after 10 minutes, the reaction was poured into brine. The addition of water produced a bilayer which separated, and the aqueous phase was extracted repeatedly with CH2Cl2. The combined organic layers were dried over anhydrous MgSO 4, and concentrated in vacuo to yield 8.95 grams (88 percent) of a white solid, which was immediately absorbed in MeOH (100 milliliters). Na2HP04 (11.4 grams, 80.3 mmol) was added, and the resulting aqueous slurry was cooled to 0 ° C before the addition of Na-Hg (6 percent, 14.5 grams, 37.8 mmol) in portions. After aging at room temperature overnight, H20 (30 milliliters) was added, and the reaction was filtered through a pad of Celite. The MeOH was removed in vacuo, and the aqueous residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to a yellow oil, which was purified by chromatography on Si02 (0 to 15 percent EtOAc / hexanes) to provide 2.14 grams (34 percent) of Compound 35 as a colorless oil (LC / MS m / z: 531.2 (M + Na) +). Compound 36 Compound 35 (1.73 grams, 3.4 mmol) was diluted in MeOH (7.5 milliliters), and 10 percent Pd / C (0.36 grams, 0.34 mmol) was added. The atmosphere was replaced with a balloon of H2, and the reaction mixture was allowed to age at room temperature. After 2 hours, the reaction mixture was filtered through a pad of Celite, the filtrate was washed several times with MeOH, and the combined organic layers were concentrated in vacuo, to provide 1.45 grams (83 percent) of Compound 36 , as a colorless oil (LC / MS m / z: 533.2 (M + Na) +), which was used in the following procedures without further purification.
Compound 37 Compound 36 (0.528 grams, 1.03 mmol) was diluted in tetrahydrofuran (3 milliliters), and added to the liquefied ammonia (approximately 20 milliliters) at -35 ° C. Small pieces of Na were added, until a blue color persisted. After 1.5 hours, solid NH4CI was added in portions, until the remaining Na was destroyed, and the ammonia was allowed to escape at room temperature. Water and EtOAc (20 milliliters each) were added, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to provide 0.395 grams (91 percent) of Compound 37 as an amorphous white solid, which was used without further purification in the following procedures ( LC / MS m / z: 421.1 (M + H) +; 443.2 (M + Na) +). Compound 38 Compound 37 (0.362 grams, 0.861 mmol) was diluted in CH2Cl2 (03.2 milliliters). Trifluoroacetic acid (0.8 milliliters) was added, and the clear solution was allowed to age overnight. Following concentration in vacuo, the residue was azeotropically distilled with toluene several times to remove residual trifluoroacetic acid. 0.382 grams (99 percent) of the bis-trifluoroacetate salt of Compound 38 was collected as a colorless oil, which was used without further purification (LC / MS m / z: 221.1 (M + H) +).
Scheme 15 Example M Example N I. Carbonate 16, DIPEA, MeCN; II. Acid 29, EOC, HOBt, DIPEA, THF. Compounds 39 and 40 Compound 38 (0.382 grams, 0.852 millimoles) was diluted in MeCN (10 milliliters), and N, N-di-isopropyl-ethyl-amine (0.60 milliliters, 3.41 millimoles) was added, followed by a Solution of Compound 16 in MeCN (1.5 milliliters). The clear yellow solution was left to age at room temperature for 4 hours, and the volatiles were removed in vacuo. The residue was taken up in 3/1 CHCI3 / IPEA (volume / volume, 13 milliliters), and treated with saturated Na2CO3 (3 milliliters). The resulting suspension was diluted with H20 (3 milliliters), and the aqueous phase was completely extracted with 3/1 CHCl3 / IPA. The combined organic layers were dried over a 3/2 (w / w) mixture of anhydrous Na 2 SO / Na 2 C0 3, and concentrated in vacuo. Chromatography on Si02 (0 to 20 percent MeOH / CH2Cl2) gave 0.043 grams (14 percent) of Compound 39, as a colorless film (LC / MS m / z: 362.1 (M + H) +), and 0.105 grams (34 percent) of Compound 40, as a colorless film (LC / MS m / z: 362.1 (M + H) +). Example M A flask was charged with Compound 39 (0.048 grams, 0.133 mmol), and Compound 29 was added as a 0.2M solution in tetrahydrofuran (0.8 milliliters, 0.160 mmol). Tetrahydrofuran (1 milliliter) was added, followed by DIPEA (0.026 milliliters, 0.145 millimoles), HOBt (0.022 grams, 0.160 millimoles), and finally EDC (0.028 milliliters, 0.160 millimoles). The clear colorless solution was left to age overnight. The volatiles were removed in vacuo, and the residue was passed through chromatography on Si02 (0 to 20 percent MeOH / CH2CI2). Fractions containing the desired compound were concentrated in vacuo, and subjected to purification by LC / MS preparation, to provide 0.018 grams (20 percent) of Example M, as a colorless film. LC / MS m / z: 657.2 (M + H) +; H-NMR (CDCl 3, 300 MHz) d 8.95 (s, 1 H); 7.88 (br s, 1H); 7.27-7.04 (m, 5H); 7.04 (s, 1H); 6.60-6.20 (m, 2H); 5.22 (m, 2H); 5.12 (d, J = 9.3 Hz, 1H); 4.50 (m, 2H); 4.01 (br s, 1H); 3.83 (m, 2H); 3.38 (m, 1H); 3.10-2.94 (m, 3H); 2.74 (m, 2H); 2.23 (m, 1H); 1.64-1.15 (m, 8H); 1140 (d, J = 6.9 Hz, 6H); 0.96 (m, 6H); 0.83 (t, J = 6.9 Hz, 3H). Example N Example N was prepared using procedures similar to those used for the preparation of Example M, using the following reagents: Compound 40 (0.055 grams, 0.152 millimoles); Compound 29 (0.92 milliliters of a solution in tetrahydrofuran 0.2M, 0.183 millimoles); tetrahydrofuran (1 milliliter); DIPEA (0.040 milliliters, 0.228 millimoles); HOBt (0.025 grams, 0.182 millimoles); EDC (0.032 milliliters, 0.182 millimoles). 0.087 grams (87 percent) of Example N was isolated as a colorless film (LC / MS m / z: 657.2 (M + H) +; H-NMR (CDCl 3, 300 MHz) d 8.84 (s, 1H); (s, 1H), 7.27-7.04 (m, 5H), 7.04 (s, 1H), 6.28 (br s, 1H), 6.12 (br s, 1H), 5.25 (m, 2H), 5.11 (d, J = 9.0 Hz, 1H), 4.62-4.32 (m, 2H), 4.19 (m, 1H), 4.01 (br s, 1H), 3.53 (m, 1H), 3.10-2.90 (m, 3H), 2.72 (d) , J = 6.0 Hz, 2H), 2.29 (m, 1H), 1.65-1.18 (m, 8H), 1.39 (d, J = 6.9 Hz, 6H), 1.00-0.78 (m, 9H), Preparation of Examples O and P Scheme 16 I. TCDI / THF / 65 ° C; II. P (OEt) 3/160 ° C; III. H2 > Pd / C at 10 percent. Compound 41 Compound 41 was prepared following the procedure described in J. Org. Chem. 1996, 61, 444-450.
Compound 42 A mixture of Compound 41 (1.73 grams, 3 mmol) and 1,1'-thiocarbonyl-d'-imidazole (1.14 grams, 6.1 mmol) in tetrahydrofuran (60 milliliters) was heated at 65 ° C for 72 hours . The solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and washed successively with 1N HCl, water, and brine, and dried over gSO. Purification by flash column chromatography (silica gel, hexanes / EtOAc = 1/1) gave Compound 42 (980 milligrams), m / z: 611.1 (M + H) +. Compound 43 A mixture of Compound 42 (980 milligrams) and triethyl phosphite (10 milliliters) was heated at 160 ° C for 14 hours. The excess reagent was removed under reduced pressure. Recrystallization from a mixture of hexanes (11 milliliters) and EtOAc (3.6 milliliters) gave Compound 57 (580 milligrams), m / z 557.3 (M + Na) +. Compound 44 A mixture of Compound 43 (580 milligrams) in i-PrOH / EtOAc (12 milliliters / 12 milliliters) was hydrogenated under high pressure (100 psi (7 kg / cm2)) for 24 hours in the presence of Pd / C to 10 percent (200 milligrams). Celite was added, and the mixture was stirred for 5 minutes. Filtration and evaporation gave Compound 44 (285 milligrams), m / z: 269.1 (M + H) +. The skilled artisan will recognize that the procedure illustrated in Scheme 16 can be employed to prepare a variety of 1,4-substituted 1,4-diamines analogous to Compound 44.
For example, a protected amine-like 2,3-dihydro-1,4-diamine can be prepared to Compound 41: Analogs of Compound 41 wherein L3, A, Ar, and P are as defined herein, and the "P" protecting group is any amine protecting group described in Protective Groups in Orqanic Svnthesis. Theodora W. Greene and Peter G. M. Wuts (John Wiley &Sons, Inc., New York, 1999, ISBN 0-471-16019-9). Then the analogs of Compound 41 can be transformed, according to the methods illustrated in Scheme 16, to form analogs of Compound 42: Analogs of Compound 42; Analogs of Compound 43: Analogs of Compound 43; Y Analogs of Compound 44: Analogs of Compound 44. It will also be recognized that stereochemical configurations different from those shown (ie, enantiomers or diastereomers) can be prepared by selecting analogs of Compound 41 having the appropriate stereochemical configuration at the chiral centers. Scheme 17 Compound 46 To the solution of Compound 45 (950 milligrams, 3.5 mmol) in CH3CN (36 milliliters) at 0 ° C, Compound 16 (892 milligrams, 3.2 mmol) was added, followed by di-isopropyl-ethyl-amine ( 1.2 milliliters, 7 millimoles). The mixture was stirred for 12 hours at 25 ° C. The mixture was diluted with EtOAc, and washed successively with saturated Na 2 CO 3, water, and brine. Purification by chromatography flash column (silica gel, 100 percent EtOAc to CH2Cl2 / MeOH = 4/1) gave Compound 46 (770 milligrams), m / z 410.1 (M + H) +. The skilled practitioner will recognize that the method illustrated in Scheme 17 can be employed to prepare a variety of compounds analogous to Compound 46. For example, 1,4-diamines analogous to Compound 44 can be prepared as discussed above: Analogs of Compound 44. Then the analogs of Compound 44 can be reacted with analogs of Compound 16: Analogs of Compound 16, wherein Z2, X, and R9 are as defined herein), to form analogs of Compound 46: It will also be recognized that stereochemical configurations different from those shown (i.e., enantiomers or diastereomers) can be prepared by selecting analogs of Compound 44 having the appropriate stereochemical configuration at the chiral centers. Scheme 18 I. CH2Cl2 / 25 ° C; II. to. NaOH / dioxane / H2Q; b. HCI; III. amine 46 / EDC / HOBt; IV. to. TFA; b. NaOH Compound 47 Compound 47 is commercially available in TCI. Compound 48 To a solution of Compound 9 (500 milligrams, 3 mmol) in CH 2 Cl 2 (3 milliliters), Compound 47 (500 milligrams, 2.5 mmol) was added. The mixture was stirred for 14 hours. The purification by flash column chromatography (hexanes / EtOAc = 1 / 1.5) gave Compound 48 (242 milligrams), m / z 372.1 (M + H) +. Compound 49 To a solution of Compound 48 (240 milligrams, 0.65 millimoles) in dioxane (4 milliliters) and water (4 milliliters), sodium hydroxide (40 milligrams, 1 millimole) was added. The mixture was stirred for 1 hour, and acidified with 4N HCl in dioxane (= .25 milliliters, 1 millimole). The mixture was extracted with EtOAc, and the organic phase was dried with MgSCv. The concentration gave Compound 49 (200 milligrams), m / z 356.2 (M-H) +. Example OA a solution of the corresponding acid 49 (30 milligrams, 0.08 millimoles) and Compound 46 (22 milligrams, 0.05 millimoles) in tetrahydrofuran (1 milliliter), were added HOBt (15 milligrams, 0.11 millimoles), EDC (20 microliters, 0.11 mmol), and di-isopropyl-ethyl-amine (0.2 milliliters). The mixture was stirred for 12 hours, and concentrated. Purification by flash column chromatography (hexanes / EtOAc = 1/5 to 0/100) gave Example O (17 milligrams), m / z: 749.3 (M + H) +. Example T To Example O (17 milligrams) was added trifluoroacetic acid (2 milliliters). The mixture was stirred for 3 hours, and concentrated. The mixture was diluted with tetrahydrofuran (2 milliliters), and a 1.0N NaOH solution was added to a pH of 11. The mixture stirred for 10 minutes, and extracted with EtOAc. The organic phase was washed with water and brine. Purification by flash column chromatography (EtOAc) gave Compound T (12 milligrams). 1 H-NMR (CDCl 3) d 8.76 (1 H, s), 7.79 (1 H, s), 7.25-6.9 (11 H, m), 6.51 (1 H, broad), 5.42 (1 H, m), 5.18 (2 H, m), 4.42 (2 H, m), 4.22 (1 H, m), 4.10 (1 H, m), 3.95 (1 H, m), 3.79 (1 H, m), 3.58 ( 1 H, m), 3.23 (1 H, m), 2.93 (3 H, s), 2.9-2.5 (4 H, m), 1.6-1.2 (10 H, m); m / z: 693.2 (M + H) +. Preparation of Examples Q, R, v S Scheme 19 I. CDI, DIPEA, CH2CI2; II. LiOH, THF / H20; III. Compound 8, DIPEA, EDC, HOBt, THF; IV. to. HCI / dioxane; b. Na2C03; V. (BrCH2CH2) 20, NaHCO3, DMF. Compound 50 Compound 50 is commercially available from Chem.
Impex International, and was used without further purification. Compound 51 Compound 50 (7.0 grams, 26.0 mmol) was dissolved in CH2Cl2 (330 milliliters), and 1, 1 -carbonyl-di-imidazole (4.22 grams, 26.0 mmol) was added, followed by i-Pr2NEt (19 milliliters, 104 millimoles). The solution was stirred at 25 ° C for 12 hours. Compound 9 (4.44 grams, 26.0 mmol) was dissolved in 20 milliliters of CH2Cl2, and added to the reaction mixture. The solution was stirred at 25 ° C for 7 hours. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate, and washed with water and brine. The organic layers were dried (Na2SO4), filtered, and evaporated. Purification by Combi-Flash® (stationary phase: silica gel, gradient from 66 to 100 percent EtOAc / hexane) gave Compound 51 (7.34 grams), m / z: 429.0 (M + H) +. Compound 52 Compound 51 (7.34 grams, 17.13 mmol) was dissolved in tetrahydrofuran (90 milliliters), and 1 M aqueous LiOH (35 milliliters) was added. The mixture was stirred at 25 ° C for 0.5 hours. The reaction was quenched with 1M HCl (51 milliliters), and the mixture was adjusted to a pH of 2. The mixture was extracted with ethyl acetate. The organic layers were dried over Na 2 SO 4, filtered, and evaporated, to provide Compound 52 (7.00 grams). Compound 52 recovered was used in the next step without further purification. m / z: 415.0 (M + H) +. The skilled practitioner will recognize that the procedure illustrated in Scheme 19 can be employed to prepare a variety of compounds analogous to Compounds 51 and 52. For example, amines analogous to Compound 9 can be reacted with the appropriate amino ester analogous to Compound 50: Analog of Compound 9 Analogue of Compound 50 to form compounds analogous to Compound 51, which are further reacted to form compounds analogous to Compound 52: Analogs of Compound 51 Analogs of Compound 52 wherein R1, R2, R7, R8, and Y are as defined herein. It will also be recognized that stereochemical configurations different from those shown (ie, enantiomers or diastereomers) can be prepared by selecting Analogs of Compound 50 having the appropriate stereochemical configuration at the chiral center. Example Q Compound 52 (2.57 grams, 6.21 mmol) was dissolved in tetrahydrofuran (67 milliliters). Compound 8 (2.10 grams, 5.13 millimoles) was added, followed by HOBt (1.04 grams, 7.70 millimoles), i-Pr2NEt (3.67 milliliters, 20.52 millimoles), and EDC (1.82 milliliters, 10.26 millimoles). The mixture was stirred at 25 ° C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel, eluent: 5 percent i-PrOH / CH2Cl2) gave Example Q (3.02 grams), m / z: 806.2 (M + H) +. Example R Example Q (3.02 grams, 3.74 mmol) was suspended in a solution of 4.0 N HCI / dioxane (30 milliliters), and stirred at 25 ° C for 3 hours. The solvent was removed under reduced pressure, and Et20 was poured into the reaction mixture. The resulting suspension was stirred vigorously for 1.5 hours. The solid was allowed to settle, and the ether layer was decanted. Washing of the precipitate with Et20 was repeated twice more. The product was dried under vacuum to provide a white solid (3.18 grams, quantitative yield). To the previous solid (3.18 grams) was added a saturated aqueous solution of Na 2 CO 3 with stirring, until the solid disappeared. The aqueous solution was extracted with ethyl acetate. The organic phases were dried over Na 2 SO 4, filtered, and dried. evaporated, to provide Example R as a yellow foam (2.44 grams, 81 percent). The recovered Example R was used without further purification in the next step, m / z: 706.1 (M + H) +. Example S Method I: Example R (1.00 grams, 1.42 mmol) was dissolved in dimethyl formamide (20 milliliters), and bromine-ethyl ether (196 microliters, 1.56 mmol) was added dropwise, followed by NaHCO 3 (0.239 grams). , 2.84 millimoles). The reaction mixture was stirred at 25 ° C for 2 hours. The solution was heated to 65 ° C, and stirred for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with EtOAc, and washed sequentially with water and brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated. Purification by reverse phase HPLC (Phenomenex Synergi®, Comb-HTS Column, eluent: 5 to 95 percent CH3CN / water) gave Compound 70 (580 milligrams, 53 percent). 1 H NMR (CDCl 3) d 8.98 (s, 1 H); 7.90 (s, IH); 7.75 (m, 1H); 7.40-7.00 (m, 11H), 6.55 (br s, 1H); 5.58 (m, 1H); 5.28, 5.19 (dAB> J = 14 Hz, 2H); 4.70-4.37 (m, 3H); 3.99 (m, 5H); 3.76 (br s, 1H); 3.65-3.30 (m, 3H); 2.97 (m, 5H); 2.90-2.60 (m, 6H); 2.28 (br s, 1H); 1.91 (br s, 1H); 1.60-1.30 (m, 10H). m / z: 776.2 (M + H) +.
Method II: Scheme 20 53 54 I. Nal04, H20 Compound 54 Compound 54 was prepared following the procedure described in J. Med. Chem. 1993, 36, 1384 (incorporated herein by reference in its entirety for all purposes). To a solution of Compound 53 (0.550 grams, 5.28 millimoles) (Sigma Aldrich) in H20 (8.8 milliliters) at 0 ° C, Nal04 (1.016 grams, 4.75 millimoles) was added. The mixture was allowed to slowly warm to 25 ° C, and was stirred for 12 hours. Solid NaHCO3 was added to the reaction mixture to a pH of 7. CHCl3 (16 milliliters) was added, and the mixture was allowed to stir for 5 minutes. The mixture was filtered, and the solid was washed with CHCl3 (6 milliliters). The combined solution of H20 / CHCl3 was used directly in the next step without further purification. Scheme 21 NH: 2 I. NaBH3CN / CH3CN / H20 Example S To a solution of Example R (70 milligrams, 0.1 mmol) in CH3CN (5 milliliters), sodium cyano-borohydride (50 milligrams) in water (5 mmol) was added. A solution of Dialdehyde Compound 54 (0.6 mmol) in CHCl3 / H20 (4 milliliters / 1 milliliter) was added to the above mixture. The mixture was stirred for 12 hours, and basified with a saturated solution of NaHCO 3. The mixture was extracted with EtOAc, and the organic phase was washed with water and brine, and dried over Na2SO4. Purification by reverse phase HPLC (Phenomenex Synergi®, Comb-HTS column) gave Example S (57 milligrams). Method III Scheme 22 I. TFA, CH2Cl2; II. Compound 54, NaBH3CN, H20 / CH3CN; III. LiOH, THF / H20; IV. Compound of amine 8, DIPEA, EDC, HOBt, THF. Compound 55 Compound 51 (0.28 grams, 0.66 mmol) was dissolved in CH2Cl2 (4 milliliters), and trifluoroacetic acid (1 milliliter) was added dropwise. The reaction was allowed to stir at 25 ° C for 1 hour. The solvent was removed under reduced pressure to provide Compound 55 (0.39 grams), m / z: 329.0 (M + H) +. Compound 56 To a solution of Compound 55 (0.39 grams, 0.89 mmol) in CH3CN (45 milliliters), NaBH3CN (0.45 grams, 7.12 mmol) and H20 (45 milliliters) were added. A solution of Compound 54 (0.55 grams, 5.34 mmol) in CHCl3 / H20 (40 milliliters) was added. The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was made basic with saturated aqueous Na 2 CO 3, and extracted in sequence with ethyl acetate and dichloromethane. The combined organic layers were washed in sequence with H20 and brine, dried over Na2SO4, filtered, and evaporated. Purification by Combi-Flash® (stationary phase: silica gel; eluent: gradient of 0 to 10 percent MeOH / CH2Cl2) gave Compound 56 (0.17 grams), m / z: 399.1 (M + H) +. Compound 57 Compound 56 (377 milligrams, 0.95 mmol) was dissolved in tetrahydrofuran (4 milliliters), and aqueous LiOH (1.90 mmol) was added. milliliters). The mixture was stirred at 25 ° C for 1 hour. The reaction was neutralized with 1M HCl. The tetrahydrofuran was removed under reduced pressure, and the aqueous solution was lyophilized to provide Compound 57 (365 milligrams). The material was used directly in the next step without further purification, m / z 385.1 (M + H) +. Example S Example S (185 milligrams, 57 percent) was prepared following the same procedure as for Example Q, except that Compound 57 (160 milligrams, 0.42 millimoles) was used in place of Compound 52. Mass m / z: 776.2 (M + H) +. The skilled practitioner will recognize that the procedure illustrated in Scheme 22 can be employed to prepare a variety of compounds analogous to Compounds 55 through 57: Analogs of Compound 51 Analogs of Compound 55 Analogs of Compound 56 Analogs of Compound 57 I. TFA, CH2Cl2; II. Ex. R, NaBH3CN, H20 / CH3CN; III. LiOH, THF / H20. wherein R7, R8, and Y are as defined herein. It will also be recognized that they can be prepared stereochemical configurations different from those shown (ie, enantiomers or diastereomers), by selecting analogs of Compound 51 having the appropriate stereochemical configuration at the chiral center. Method IV Scheme 23 I. a. NaOH / H20; b. BnBr; II. S03 / pyridine; III. morpholine / NaBH (OAc) 3; IV. to. NaOH; b. HCI. Compound 59 To a solution of Compound 122 (33 grams, 112 mmol) (see Scheme 69) in ethanol (366 milliliters) at 0 ° C, a solution of sodium hydroxide (4.7 grams, 117 mmol) in water was added. (62 milliliters). The mixture was stirred for 1 hour at 25 ° C, and the solvents were removed under reduced pressure. The mixture was coevaporated with ethanol (400 milliliters, three times), and dried at 60 ° C for 2 hours under a high vacuum, to give a white solid. To the solution of the above solid in dimethyl formamide (180 milliliters), benzyl bromide (16.2 milliliters, 136 mmol) was added. The mixture was stirred for 16 hours in the dark, and quenched with water (300 milliliters). The mixture was extracted with EtOAc (300 milliliters, four times). The combined organic phase was washed with water (five times) and brine, and dried over Na2SO4. The concentration gave Compound 59 (48 grams), which was used in the next step without further purification. Compound 60 A mixture of Compound 59 (33 grams, 74 mmol) in dimethyl sulfoxide (225 milliliters) and Et 3 N (36 milliliters) was stirred for 30 minutes. The mixture was cooled to 0-10 ° C, S03-pyridine (45 grams) was added, and stirring was continued for 60 minutes. Ice (300 grams) was added, and the mixture was stirred for 30 minutes. EtOAc (300 milliliters) was added, and saturated Na 2 CO 3 was added until the pH was 9 to 10. The organic phase was separated from the aqueous phase, and the aqueous phase was extracted with EtOAc (300 milliliters, twice). The combined organic phases were washed with saturated Na 2 CO 3 (twice), water (three times), and brine. The mixture was dried over Na2SO4 > and concentrated, to give Compound 60 (32 grams), which was used directly in the next step without further purification. Compound 61 To a solution of Compound 60 (32 grams) in CH3CN (325 milliliters) was added morpholine (12.9 milliliters, 148 millimoles), with a water bath around the reaction vessel, followed by HOAc (8.9 milliliters, 148 millimoles ), and NaBH (OAc) 3 (48 grams, 222 mmol). The mixture was stirred for 12 hours. CH3CN stirring under reduced pressure, and the mixture was diluted with EtOAc (300 milliliters). Saturated Na 2 CO 3 was added until the pH was from 9 to about 10. The organic phase was separated from the aqueous phase, and the aqueous phase was extracted with EtOAc (300 milliliters, twice). The combined organic phases were washed with saturated Na 2 CO 3 (twice), water (once), and brine (once). The mixture was dried over Na2SO4. The resulting residue was concentrated and purified by silica gel column chromatography (EtOAc to DCM / iPrOH = 10/1), to give Compound 61 (30 grams). Compound 57 To a solution of Compound 61 (26.5 grams, 56 mmol) in ethanol (160 milliliters) at 0 ° C, was added a solution of sodium hydroxide (2.5 grams, 62 mmol) in water (30 milliliters). The mixture was stirred for 1 hour at 25 ° C, and the solvents were removed under reduced pressure. The mixture was diluted with water (200 milliliters), and washed with CH2Cl2 (6 milliliters, six times). The water phase was acidified with 12 N HCl (5.2 milliliters), and dried under reduced pressure, to give Compound 57 (22 grams). Example S Compound 57 was converted to Example S using the procedure described in Method III above. Preparation of Compounds T and U Goes. CH3COCI, DIPEA, CH2CI2; Vb. CH3COOH, DIPEA, EDC, HOBt, THF; SAW. sCI, DIPEA, CH2CI2. Compounds: Example T: X = NHAc. Example U: X = NHMs.
Example T Method I The hydrochloride salt of Example R (100 milligrams, 0.13 mmol) was suspended in CH2Cl2 (2 milliliters), and dissolved by the addition of iPr2NEt (69 microliters). Acetyl chloride (11 microliters) was added dropwise, and the mixture was allowed to stir at 25 ° C for 4 hours. The solvent was removed in vacuo. Purification of the residue by flash column chromatography (stationary phase: silica gel, eluent: 8 percent iPrOH / CH2Cl2) gave Example T (39 milligrams, 40 percent), m / z: 748.2 (M + H) +. 1 H NMR (CDCl 3) d 8.85 (s, 1 H), 7.87 (s, 1 H), 7.73 (s, 1 H), 7.40-7.00 (m, 13 H), 6.45 (br s, 1 H), 5.70 (m, 1 H) , 5.32, 5.22 (dAB, J = 13 Hz, 2H), 4.51 (s, 2H), 4.20-3.90 (m, 4H), 3.78 (m, 1H), 3.38 (m, 2H), 3.20-2.50 (m , 8H), 1.95 (s, 4H), 1.82 (m, 2H), 1.41 (m, 6H). Method II A saturated aqueous solution of Na 2 CO 3 was added to the hydrochloride salt of Example R (3.18 grams, 3.46 mmol), with stirring, until the solid disappeared. The aqueous solution is extracted with ethyl acetate. The organic phases were dried over Na 2 SO 4, filtered, and evaporated, to give Example R as a yellow foam (2.44 grams, 81 percent). This material was used without further purification in the next step, m / z: 706.1 (M + H) +. Example R (300 milligrams, 0.43 mmol) was dissolved in tetrahydrofuran (5.5 milliliters). Acetic acid (37 microliters, 0.64 millimoles) was added, followed by HOBt (85 milligrams, 0.64 millimoles), iPr2NEt (304 microliters, 1.70 millimoles), and EDC (151 microliters, 0.85 millimoles). The reaction mixture was allowed to stir at 25 ° C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with EtAOc, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated. Purification by Combi-Flash® (stationary phase: silica gel, eluent: 10 percent MeOH / CH 2 Cl 2) gave Example T (249 milligrams, 77 percent), m / z: 748.2 (M + H) +. Example U Example R (100 milligrams, 0.13 mmol) was suspended in CH2Cl2 (2 milliliters), and dissolved by the addition of iPr2NEt (69 microliters). Metan-sulfonyl chloride (12 microliters) was added dropwise, and the mixture was allowed to stir at 25 ° C for 4 hours. The solvent was removed in vacuo. Purification of the residue by flash column chromatography (stationary phase: silica gel, eluent: 8 percent iPrOH / CH2CI2) gave Example U (55 milligrams, 54 percent), m / z: 784.2 (+ H) +. 1 H NMR (CDCl 3) d 8.90 (s, 1H); 7.88 (s, 1H); 7.40-7.00 (m, 12H); 6.54 (br s, 1H); 6.19 (br s, 1H); 5.25 (s, 2H); 4.53 (s, 2H); 4.38 (m, 1H); 4.12 (m, 1H); 3.79 (m, 1H); 3.79 (m, 1H); 3.48 (m, 1H); 2.99 (s, 3H); 2.90 (m, 3H); 2.73 (m, 6H); 2.00 (m, 1H); 1.79 (m, 1H); 1.60-1.18 (m, 10H). Preparation of Examples V. W. X. and Y Scheme 25 I. Compound 46, DIPEA, EDC, HOBt, THF; II. HCI / dioxane; Illa CH3COCI, DIPEA, CH2CI2; lllb. CH3COOH, DIPEA, EDC, HOBt, THF IV. MsCI, DIPEA, CH2CI2. Compounds: Example X: X = NHAc. Example Y: X = NHMs.
Example V Example V (692 milligrams) was prepared following the same procedure used to prepare Example Q, except that Example 46 was used in place of Compound 8. m / z: 806.2 (M + H) +. Example W Example W (770 milligrams, quantitative yield) was prepared following the same procedure for Example R, except that Example V was used instead of Example Q. m / z: 706.2 (M + H) +. 1 H NMR (CD3OD) d 9.86 (s, 1H), 8.23 (s, 1H), 7.66 (s, 1H), 7.40-7.00 (m, 10H), 5.29, 5.17 (dAB, J = 13 Hz, 2H), 4.80-4.60 (m, 2H), 4.18 (s, 2H), 4.26 (m, 2H), 3.67 (br s, 1H), 3.55 (m, 2H), 3.03 (m, 3H), 2.90-2.60 (m , 8H), 2.53 (s, 2H), 2.00-1.80 (m, 2H), 1.85-1.30 (m, 10H). Compound 59 Method I Example X (107 milligrams, 55 percent) was prepared following the procedure of Method I for Example T, except that Example W was used in place of Example R. m / z: 748.2 (M + H ) + 1 H NMR (CDCl 3) d 8.80 (s, 1 H), 7.40 (m, 1 H), 7.38-7.00 (m, 10 H), 6.94 (s, 1 H), 6.30 (m, 2 H), 5.75 (m, 1 H), 5.30, 5.23 (dAB, J = 13 Hz, 2H), 4.54, 4.46 (dAB, J = 8 Hz, 2H), 4.20-3.90 (m, 2H), 3.74 (br s, 1H), 3.46 (br s, 1H), 3.28 (m, 1H), 2.98 (s, 3H), 2.83 (m, 3H), 2.72 (m, 1H), 2.62 (m, 1H), 2.05-1.20 (m, 15H). Method II Example X (205 milligrams, 65 percent) was prepared following the procedure of Method II for Example T, except that Example W was used in place of Example R. m / z: 748.2 (M + H) +. Example Y Example Y (106 milligrams, 50 percent) was prepared following the same procedure for Example U, except that Example W was used in place of Example R. m / z: 784.2 (M + H) +. 1 H NMR (CDCl 3) d 7.85 (s, 1 H), 7.40-7.05 (m, 10 H), 6.98 (s, 1 H), 6.22 (br s, 1 H), 5.78 (s, 1 H), 5.25 (m, 4 H) , 4.29 (m, 2H), 4.33 (br s, 1H), 4.12 (br s, 1H), 3.77 (br s, 1H), 3.10 (br s, 1H), 2.98 (s, 3H), 2.90 (s) , 3H), 2.73 (m, 6H), 2.00-1.20 (m, 12H). Preparation of Examples Z-AD Scheme 26 HOBt, THF.
Compound 62 The tert-butyl 2-aminoethyl carbamate (62) is commercially available from Aldrich, and was used without further purification. Compound 63 To a solution of Compound 62 (2.0 mmol) in CH3CN (15 milliliters) was added Compound 16 (1.82 millimoles), followed by the addition of N, N-di-isopropyl-ethyl-amine (0.61 milliliters). The mixture was stirred at 25 ° C for 12 hours. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic layers were dried with Na 2 SO 4, filtered, and evaporated. Purification by Combi-Flash® (stationary phase: silica gel; eluent: gradient from 25 to 100 percent EtOAc / hexane) gave Compound 63. m / z: 301.9 (M + H) +. Compound 64 To a solution of Compound 63 (1.05 mmol) in EtOAc (3 milliliters) was added a solution of 4N HCl / d-oxane 81.1 milliliters). The mixture was allowed to stir at 25 ° C for 12 hours. The solvent was removed under reduced pressure, and Compound 64 was obtained as a white powder. This material was used in the next step without further purification, m / z: 216.0 (M + H) +. Example Z Compound 64 (70 milligrams, 0.29 mmol) was dissolved in tetrahydrofuran (2.2 milliliters). Compound 29 (91 milligrams, 0.29 mmol) was added to the reaction flask as a 1.0M solution in tetrahydrofuran, followed by HOBt (59 milligrams, 0.44 millimoles), N, N-di-isopropyl-ethyl-amine (207 microliters, 1.16 millimoles), and EDC (103 microliters, 0.58 millimoles). The reaction was allowed to stir for 12 hours at 25 ° C, and concentrated under reduced pressure. The residue was diluted with EtOAc, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic layers were dried with Na 2 SO 4, filtered, and evaporated. Purification by Combi-Flash® (stationary phase: silica gel, eluent: gradient of 0 to 10 percent MeOH / CH2CI2) gave Example Z (54 milligrams, 38 percent), m / z: 497.1 (M + H) +. 1 H NMR (CDCl 3) d 8.78 (s, 1H); 7.83 (s, 1H); 6.99 (s, 1H); 6.80 (br s, 1H); 6.22 (br s, 1H); 5.87 (br s, 1H); 5.25 (s, 2H); 4.43 (s, 2H); 3.97 (m, 1H); 3.34 (m, 4H); 2.95 (s, 3H); 2.22 (m, 2H); 1.38 (d, J = 7 Hz, 6H); 0.97 (d, J = 7 Hz, 6H). Example AA Example AA was prepared following the procedures for steps I to III (Scheme 20) for Example Z, with the exception that 3-amino-propyl-carbamate terbutyl was used in place of 2-amino-ethyl -Terbutyl carbamate (Compound 62). After purification by Combi-Flash®, 38 milligrams (34 percent) of Example AA was obtained. m / z: 511.1 (M + H) +. 1 H NMR (CDCl 3) d 8.78 (s, 1H); 7.84 (s, 1H); 6.96 (s, 2H); 6.17 (br s, 1H); 5.80 (m, 1H); 5.26 (m, 2H); 4.44 (s, 2H); 4.09 (m, 1H); 3.40-3.10 (m, 5H); 2.97 (s, 3H); 2.20 (m, 1H); 1.60 (m, 2H); 1.36 (d, J = 7 Hz, 6H); 0.96 (d, J = 7 Hz, 6H).
Example AB Example AB was prepared following the procedures for steps I to III (Scheme 20) for Example Z, with the exception that terbutyl 1-piperazine carboxylate was used in place of 2-amino-ethyl-carbamate of terbutyl (Compound 62). After purification by Combi-Flash®, 64 milligrams (45 percent) of Example AB were obtained. m / z: 523.1 (M + H) +. 1 H NMR (CDCl 3) d 8.82 (s, 1 H); 7.89 (s, 1H); 6.96 (s, 1H); 5.93 (br s, 1H); 5.35 (s, 2H); 4.62 (m, 1H); 4.50 (m, 2H); 3.80-3.40 (m, 8H); 3.34 (m, 1H); 3.00 (s, 3H); 1.97 (m, 1H); 1.40 (d, J = 7 Hz, 6H); 0.96, 0.93 (d, J = 7 Hz, 6H). Example AC Example AC was prepared following the procedures for steps I to III (Scheme 20) for Example Z, with the exception that 4-amino-piperidine-tert-butyl carbonate was used in place of 2-amino-ethyl -Terbutyl carbamate (Compound 62). After purification by Combi-Flash®, 60 milligrams (44 percent) of Example AC was obtained. m / z: 537.1 (M + H) +. 1 H NMR (CDCl 3) d 8.82 (s, 1H); 7.87 (s, 1H); 6.97 (s, 1H); 5.82 (br s, 1H); 5.30 (m, 3H); 4.80-4.40 (m, 5H); 4.03 (m, 1H); 3.72 (br s, 1H); 3.34 (m, 1H); 3.18 (m, 1H); 3.01 (s, 3H); 2.79 (m, 1H); 2.20-1.90 (m, 4H); 1.40 (d, J = 7 Hz, 6H); 0.97, 0.90 (d, J = 7 Hz, 6H). Example AD Example AD was prepared following procedures I to III for Example Z, with the exception that the 4-piperidinyl-tertiary butyl carbamate was used in place of the 2-amino-ethyl-carbamate terbutyl (Compound 62). After purification by Combi-Flash®, 49 milligrams (36 percent) of Example AD were obtained. m / z: 537.1 (M + H) +. 1 H NMR (CDCl 3) d 8.82 (s, 1H); 7.87 (s, 1H); 7.01 (s, 1H); 6.33 (br s, 1H); 6.11 (br s, 1H), 5.32 (s, 2H), 4.47 (s, 2H), 4.20-3.80 (m, 4H), 3.35 (m, 1H), 3.10-2.80 (m, 6H), 2.21 (m , 2H), 1.90 (m, 2H), 1.40 (d, J = 7 Hz, 6H), 0.97 (d, J = 7 Hz, 6H). Preparation of Examples AE-AG Scheme 27 I. CDI, DIPEA, CH2CI2; II. NaOH, THF / H20; III. Compound 8, DIPEA, EDC, HOBt, THF; IV. TFA clean; V. (Boc) 20, NH 4 HCO 3, pyridine, dioxane, DMF.
Compound 65 Compound 65 is commercially available from Chem. Impex International, and was used without further purification. Compound 66 Compound 65 (956 milligrams, 4.0 mmol) was dissolved in CH2Cl2 (45 milliliters), and 1, 1 -carbonyl-di-imidazole (648 milligrams, 4.0 mmol) was added, followed by i-Pr2NEt (2.8 milliliters, 16 millimoles). The solution was stirred at 25 ° C for 12 hours. Compound 9 (679 milligrams, 4.0 mmol) was dissolved in CH2Cl2 (5 milliliters), and added to the reaction. The mixture was allowed to stir for 5 hours. Then the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, and filtered through Celite. The ethyl acetate was then removed in vacuo. Purification by flash column chromatography (stationary phase: silica gel; eluent: EtOAc) gave Compound 66 (841 milligrams), m / z: 400.0 (M + H) +. Compound 67 Compound 66 (841 milligrams, 2.11 mmol) was dissolved in tetrahydrofuran (9 milliliters), and 2N aqueous NaOH was added. The solution was stirred at 25 ° C for 2 hours. The reaction was adjusted to a pH of 2 with 1N HCl. The mixture was extracted with ethyl acetate, dried with Na 2 SO 4, filtered, and evaporated. Compound 67 (772 milligrams) was used directly in the next step without further purification, m / z: 386.0 (M + H) +.
Example AE Compound 67 (569 milligrams, 1.48 millimoles) was dissolved in tetrahydrofuran (17 milliliters). Compound 8 (970 milligrams, 2.37 millimoles) was added, followed by HOBT (300 milligrams, 2.22 millimoles), i-Pr2NEt (1.06 milliliters, 5.92 millimoles), and EDC (0.52 milliliters, 2.96 millimoles). The mixture was stirred at 25 ° C for 36 hours. The solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel, eluent: 8 percent iPrOH / CH2Cl2) gave Example AE (3.02 grams), m / z: 777.2 (M + H) \ Example AF Example AE (100 milligrams, 0.13 mmol) was dissolved in clean trifluoroacetic acid (3 milliliters). The mixture was stirred at 25 ° C for 2 hours. The solvent was removed under reduced pressure. Purification by reverse phase HPLC (Phenomenex Synergi®, Comb-HTS column, eluent: gradient from 5 to 95 percent CH3CN / H20) gave Example AF (20 milligrams, 21 percent), m / z: 721.2 ( M + H) +. 1 H NMR (CDCl 3) d 8.92 (s, 1H); 7.91 (s, 1H); 7.40-7.00 (m, 11H); 6.41 (br s, 1H); 6.12 (br s, 1H); 5.40-5.00 (m, 3H); 4.70-4.50 (m, 3H); 4.05 (br s, 1H); 3.81 (br s, 1H); 3.51 (br s, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 6H); 1.41 (d, 7 = 7 Hz, 10H).
Example AG Example AF (70 milligrams, 0.10 mmol) was dissolved in dioxane (0.5 milliliters). Dimethylformamide (83 microliters), pyridine (25 microliters, 0.29 mmol), diterbutyl dicarbonate (27 milligrams, 0.13 mmol), and ammonium dicarbonate (15 milligrams, 0.19 mmol) were added. The mixture was stirred at 25 ° C for 48 hours, then diluted with ethyl acetate, and washed sequentially with water and brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated. Purification by reverse phase HPLC (Phenomenex Synergi®, Comb-HTS column, eluent: gradient from 5 to 95 percent CH3CN / H20 (gave Example AG (35 milligrams, 50 percent). 1H NMR (CDCl3) d 8.80 (s, 1H), 7.84 (s, 1H), 7.40-7.00 (m, 10H), 7.08 (s, 1H), 6.83 (m, 1H), 6.65 (m, 1H), 5.40-5.10 (m, 4H), 4.60-4.40 (m, 3H), 4.06 (m, 1H), 3.79 (m, 1H), 3.36 (m, 1H), 2.97 (s, 3H), 2.90-2.60 (m, 6H), 2.45 (m, 1H); 1.70-1.20 (m, 10H) Preparation of Compounds 68 and 69 Scheme 28 15 68: R = methyl. 69: R = cyclopropyl. Compound 15 Compound 15 is commercially available from Molekula, and was used without further purification.
Compound 68 Compound 15 (6.81 grams, 59.1 mmol) was dissolved in CH3CN (340 milliliters), and methan-sulfonyl chloride (7.03 milliliters, 65.1 mmol) was added, followed by triethylamine (9.03 milliliters, 65.1 mmol). After the mixture was stirred for 20 minutes, 40 weight percent methyl amine / water (516 milliliters) was added to the reaction mixture. The solution was stirred for 12 hours at 25 ° C. The solvent was removed under reduced pressure, and the residue was partitioned between saturated aqueous Na 2 CO 3 and CH 2 Cl 2. The organic phase was separated, dried over Na 2 SO 4, filtered, and evaporated. Purification by flash chromatography (stationary phase: silica gel, eluent: 0 to 10 percent eOH / CH2Cl2) gave Compound 68 (5.07 grams), m / z: 128.9 (M + H) +. Compound 69 Compound 15 (10.0 grams, 80 mmol) was dissolved in CH3CN (500 milliliters), and methan-sulfonyl chloride (7.0 milliliters, 88 mmol) was added, followed by triethylamine (12.3 milliliters, 88 mmol). After the mixture was stirred for 2 hours, cyclopropyl-amine (140 milliliters, 2,000 millimoles) in CH 3 CN (500 milliliters) was added to the reaction mixture. The solution was stirred for 36 hours at 25 ° C. The solvent was removed under reduced pressure, and the aqueous paste was partitioned between saturated aqueous Na 2 CO 3 and 3: 1 of CH 2 Cl 2: i-PrOH. The organic phase was separated, dried over Na 2 SO 4, filtered, and evaporated. Compound 69 (12.81 grams) was used in the next step without further purification, m / z: 155.0 (M + H) +. Preparation of Examples AH and Al Scheme 29 I. DIPEA, CH2Cl2; II. LiOH, THF / HzO; III. Compound 8, HOBt, EDC, DIPEA, THF; IV. to. TFA clean; b. NaOH, THF, H20. Compound 20 Compound 68 (1.00 grams, 7.80 mmol) was dissolved in tetrahydrofuran (25 milliliters), and Compound 10e (2.51 grams, 7.09 mmol) was added, followed by?,? - dimethyl-amino-pyridine (200 milligrams, 1.63 millimoles), and triethylamine (4.34 milliliters, 31.2 millimoles). The mixture was allowed to stir at 60 ° C for 6 hours. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, and washed sequentially with aqueous Na 2 CO 3. saturated, H20, and brine. The organic layer was dried over Na 2 SO 4, filtered, and evaporated. The resulting residue was purified by Combi-Flash® (stationary phase: silica gel, eluent: gradient from 20 to 100 percent EtOAc / hexane), to give Compound 70 (2.12 grams), m / z: 343.9 (M + H) +. Compound 71 Compound 70 (2.14 grams, 6.23 mmol) was dissolved in tetrahydrofuran (25 milliliters), and 1 M aqueous LiOH (12.5 milliliters) was added. The mixture was stirred at 25 ° C for 2 hours. The reaction was quenched with 1 M HCl (15 milliliters), and the mixture was adjusted to a pH of 2. The mixture was extracted with ethyl acetate. The organic layers were dried over Na 2 SO 4, filtered, and evaporated, to provide Compound 71 (1.96 grams). This material was used in the next step without further purification, m / z: 330.0 (M + H) +. Example AH Compound 71 (43 milligrams, 0.13 mmol) was dissolved in tetrahydrofuran (1.5 milliliters). Compound 8 (50 milligrams, 0.12 millimoles) was added, followed by HOBt (24 milligrams, 0.18 millimoles), iPr2NEt (86 microliters, 0.48 millimoles), and EDC (42 microliters, 0.24 millimoles). The mixture was stirred at 25 ° C for 12 hours. The solvent was removed under reduced pressure, and the resulting residue was diluted with ethyl acetate, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated. Purification by flash column chromatography (phase stationary: silica gel; eluent: gradient of 1 to 10 percent MeOH / CH2Cl2) gave Example AH (66 milligrams), m / z: 721.2 (M + H) +. Compound Al Example AH (66 milligrams, 0.09 mmol) was dissolved in trifluoroacetic acid, and allowed to stir at 25 ° C for 3 hours. The solvent was removed under reduced pressure, and the residue was diluted with tetrahydrofuran (10 milliliters), and 2N aqueous NaOH was added, to a pH of 12. The mixture was allowed to stir for 20 minutes, and extracted with EtOAc. The organic layer was washed in sequence with water and brine, dried over Na 2 SO 4, filtered, and evaporated. Purification by flash chromatography (stationary phase: silica gel; eluent: gradient from 0 to 20 percent of i-PrOH / CH2Cl2) gave Example Al (71 milligrams, 97 percent). Al (71 milligrams, 97 percent), m / z: 665.2 (M + H) \ 1 H NMR (CDCl 3) d 8.84 (s, 1H); 8.80 (s, 1H); 7.85 (s, 1H); 7.79 (s, 1H); 7.40-7.00 (m, 10H); 6.69 (m, 1H); 5.34 (m, 1H); 5.24 (s, 2H); 4.86 (m, 2H); 4.73, 4.59 (OAB, J = 16 HZ, 2H); 4.30 (s, 1H); 4.15 (m, 2H); 3.86 (br s, 1H); 2.88 (s, 3H); 2.85-2.60 (m, 4H); 2.01 (s, 1H); 1.58 (s, 2H); 1.44 (s, 2H); 1.09 (d, J = 6 Hz, 3H). Preparation of Examples Al and AK Scheme 30 I. DIPEA, CH2Cl2; II. LiOH, THF / H20; III. Compound, EDC, DIPEA, THF; IV. to. TFA clean; b. NaOH, THF, HzO Compound 47 Compound 47 is commercially available from TCI America, and was used without further purification. Compound 72 Compound 72 was prepared following the procedure for Compound 48 (Method II), except that Compound 68 was used in place of Compound 9. Compound 73 Compound 73 was prepared following the procedure for Compound 9, except that used Compound 72 instead of Compound 48. Example AJ Example AJ (70 milligrams) was prepared following the same procedure used to prepare Example AH, with the exception that Compound 73 (41 milligrams, 0.13 millimoles) was used in place of Compound 71. m / z: 707.2 (M + H) +. Example AK Example AK (43 milligrams, 67 percent) was prepared following the same procedure used to prepare Example Al, with the exception that Example AJ (70 grams, 0.10 millimole) was used in place of Example AH. m / z: 651.2 (M + H) +. 1 H NMR (CDCl 3) d 8.83 (s, 2H); 7.84 (s, 1H); 7.79 (s, 1H); 7.40-7.00 (m, 10H); 6.65 (br s, 1H); 5.47 (br s, 1H); 5.24 (s, 2H); 4.90 (m, 1H); 4.82-4.50 (m, 2H); 4.30-4.00 (m, 3H); 3.84 (br s, 1H); 3.49 (m, 1H); 2.87 (s, 3H); 2.75 (br s, 5H); 1.60-1.20 (m, 4H). Preparation of Examples AL and AM Scheme 31 I. DIPEA, CH2Cl2; II. LiOH, THF / HzO; III. Compound 8, HOBt, EDC, DIPEA, THF; IV. to. TFA clean; b. NaOH, THF, H20. Compound 74 Compound 69 (1.56 grams, 10.1 mmol) was dissolved in CH2Cl2 (10 milliliters). Compound 47 (1.7 grams, 8.5 mmol) in CH2Cl2 (20 milliliters) was added, followed by iPr2NEt (3.02 milliliters, 16.9 millimoles). The reaction was stirred at 25 ° C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, and washed sequentially with water and brine, dried over Na 2 SO 4, filtered, and evaporated. Purification by Combi-Flash® (stationary phase: silica gel; eluent: gradient from 50 to 100 percent EtOAc / hexane) gave Compound 74 (2.92 grams), m / z: 356.0 (M + H) +. Compound 75 Compound 74 (0.97 mmol) was taken up in tetrahydrofuran (3 milliliters), and treated with freshly prepared 1 M LiOH (2 mmol), and stirred vigorously for 1 hour. The reaction was quenched with 1M HCl (2.5 mmol), and extracted with EtOAc (15 milliliters, three times). The combined organics were washed with brine (25 milliliters), dried over anhydrous Na 2 SO 4, and concentrated in vacuo, to yield 0.331 grams (quantitative) of Compound 75, as a colorless film (m / z: 342.0 (M + H) +). Example AL Example AL (2.20 grams) was prepared following the same procedure used to prepare Example AH, with the except that Compound 75 (2.00 grams, 4.88 millimoles) was used instead of Compound 71. m / z: 733.2 (M + H) +. Example AM Example AM (1.88 grams, 92 percent) was prepared following the same procedure used to prepare Example Al, with the exception that Example AL (2.20 grams, 3.01 mmol) was used instead of Example AH. m / z: 677.2 (M + H) +. 1 H NMR (CDCl 3) d 8.79 (s, 1 H); 8.72 (s, 1H); 7.82 (s, 1H); 7.77 (s, 1H); 7.40-7.00 (m, 10H); 6.59 (m, 1H); 6.31 (m, 1H); 5.23 (s, 2H); 5.00 (m, 1H); 4.72, 4.60 (dAB, J = 15 Hz, 2H); 4.18 (s, 2H); 4.03 (m, 1H); 3.84 (br s, 1H); 3.48 (m, 1H); 2.85-2.60 (m, 4H); 2.37 (br s, 2H); 1.58 (s, 2H); 1.41 (s, 2H); 0.93 (m, 2H); 0.76 (m, 2H). Scheme 32 Compound 76 Compound 76 (m / z: 117.0 (M + H) + diamine) was prepared using a procedure similar to that used to prepare Compound 25 (described in Scheme 7), except that the CBZ-L- was used. alininol in place of CBZ-D-phenyl-alininol, and step III was carried out by adding 1M HCl. Compound 77 Compound 77 (m / z: 145.0 (M + H) + diamine) was prepared using a procedure similar to that used to prepare Compound 76, except that (S) - (+) - 2-CBZ-amino-1-butanol was used in place of CBZ-D-phenyl-alininol. Compound 78 Compound 76 (7.93 mmol) is added to a solution of NaOH (16.7 mmol) in H20 (5 milliliters), which is cooled to 0 ° C, and diluted with MeCN (40 milliliters). DIPEA is added (2.1 milliliters, 11.9 millimoles). Compound 16 (7.9 mmol) is absorbed in MeCN (40 milliliters), and added to the reaction solution by dripping by means of an addition funnel for 1 hour. The resulting solution is allowed to warm to room temperature overnight. The solvent is removed in vacuo, and the residue is removed. absorbs in 3/1 of CHCI3 / IPA (50 milliliters). The resulting solution is washed with saturated Na 2 CO 3 (50 milliliters), and water is added until the aqueous layer is homogeneous. The aqueous layer is extracted with 3/1 CHCI3 / IPA (25 milliliters, three times). The combined organics are washed with saturated Na 2 CO 3 (50 milliliters), water (50 milliliters), and brine (50 milliliters), and dried over anhydrous Na 2 SO 4. The solvent is removed in vacuo, and the residue is purified by column chromatography on Si02 (100 percent EtOAc, then 0 to 20 percent MeOH / DCM), to yield 0.63 grams (31 percent) of 78 as a grayish solid, (m / z: 258.0 (M + H) +). Compound 79 Compound 79 (m / z: 286.1 (M + H) +) was prepared following the procedure for Compound 78, except that the Compound 77 in place of Compound 76. Scheme 33 AO I. Compound 79, HOBt, EDC, DI PEA, THF; II. to. TFA clean; b. NaOH, THF, HaO. Example AN Example AN (68 milligrams) was prepared following the same procedure used to prepare Example AH, with the exceptions that Compound 49 (68 milligrams, 0.19 millimoles) was used instead of Compound 71, and that it was used Compound 79 (50 milligrams, 0.18 millimoles) instead of Compound 8. m / z: 625.2 (M + H) +. Example AO Example AO (66 milligrams, 76 percent) was prepared following the same procedure used to prepare Example Al, with the exception that Example AN (43) was used. milligrams, 0.13 millimoles) instead of Example AH. m / z: 569.2 (M + H) +. 1 H NMR (CDCl 3) d 8.85 (s, 1 H); 7.89 (s, 1H); 7.08 (s, 1H); 6.81 (m, 1H); 5.29 (s, 2H); 4.87 (m, 1H); 4.63, 4.48 (dAB, 7 = 16 Hz, 2H); 4.31 (m, 1H); 4.11 (m, 1H); 3.76 (m, 2H); 3.44 (m, 2H); 3.02 (m, 4H); 1.60-1.20 (m, 14H); 1.00-0.70 (m, 6H). Preparation of Examples AP and AQ Scheme 34 AQ I. LiOH, THF / H2O; II. Compound 9, HOBt, EDC, DIPEA, THF; III. to. TFA clean; b. NaOH, THF, H20. Compound 13e Compound 13e (1.39 grams) was prepared following the same procedure used to prepare Compound 71, with the exception that Compound 12e (1.53 grams, 3.97 mmol) instead of Compound 70. m / z: 372.0 (M + H) +. Example AP The AP Example (87 milligrams) was prepared following the same procedure used to prepare Example AH, with the exception that Compound 13e (71 milligrams, 0.19 mmol) was used in place of Compound 71, and that Compound 79 (50 milligrams, 0.18 mmol) was used instead of Compound 8. m / z: 639.2 (M + H) +. Compound AQ Example AQ (61 milligrams, 76 percent) was prepared following the same procedure used to prepare Example Al, with the exception that AP Example (87 milligrams, 0.14 millimoles) was used in place of Example AH. m / z: 583.2 (M + H) +. 1 H NMR (CDCl 3) d 8.81 (s, 1H); 7.87 (s, 1H); 7.01 (s, 1H); 6.87 (m, 1H); 6.52 (s, 1H); 5.28 (m, 2H); 4.47 (m, 1H); 4.59, 4.43 (d J = 16 Hz, 2H); 4.45 (m, 1H); 4.17 (br s, 1H); 3.75 (br s, 1H); 3.52 (br s, 1H); 3.35 (br s, 1H); 3.01 (m, 3H); 2.07 (br s, 1H); 1.60-1.10 (m, 17H); 1.00-0.70 (m, 6H). Preparation of Example AR Scheme 35 I. CDI, DIPEA, CH2CI2; II. LiOH, THF / H20; III. Compound 46, DIPEA, EDC, HOBt, THF. Compound 80 Compound 80 is commercially available from Chem Impex International, and was used without further purification. Compound 81 Compound 80 (2.0 grams, 11.0 mmol) was dissolved in CH2Cl2 (170 milliliters), and 1, 1 -carbonyl-di-imidazole (1.78 grams, 11.0 mmol) was added followed by iPr2NEt (7.83 milliliters, 43.8 mmol). . The solution was left stirring at 25 ° C for 12 hours.
Compound 9 (1.86 grams, 11.0 mmol) was dissolved in 20 milliliters of CH2Cl2, and added to the reaction mixture. The solution was stirred at 25 ° C for 12 hours. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate, and washed with water and brine. The organic layers were dried over Na 2 SO 4, filtered, and evaporated. Purification by Combi-Flash® (stationary phase: silica gel; eluent: gradient from 66 percent to 100 percent EtOAc / hexane) gave Compound 81 (0.252 milligrams), m / z: 343.0 (M + H) +. Compound 82 Compound 82 (0.252 grams, 0.74 mmol) was dissolved in tetrahydrofuran (4 milliliters), and aqueous 1M LiOH (1.48 milliliters) was added. The mixture was stirred at 25 ° C for 3 hours. The reaction was quenched with 1 M HCl (2 milliliters), and the mixture was adjusted to a pH of 2. The mixture was extracted with ethyl acetate. The organic layers are dried over Na 2 SO 4, filtered, and evaporated, to provide Compound 82 (0.18 grams). This material was used in the next step without further purification, m / z: 329.1 (? +?) *. Example AR Compound 82 (182 milligrams, 0.55 millimole) was dissolved in tetrahydrofuran (7.15 milliliters). Compound 46 (225 milligrams, 0.55 millimoles) was added, followed by HOBt (112 milligrams, 0.83 millimoles), iPr2NEt (393 microliters, 2.20 millimoles), and EDC (194 microliters, 1.10 millimoles). The mixture was stirred at 25 ° C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated. Purification by flash column chromatography (stationary phase: stationary phase; silica gel; eluent: gradient of 5 to 10 percent MeOH / CH2Cl2) gave Example AR (208 milligrams, 53 percent), m / z : 720.2 (M + H) *. 1 H NMR (CDCl 3) d 8.80 (s, 1 H), 7.84 (s, 1 H), 7.40-7.00 (m, 10 H), 6.97 (s, 1 H), 6.83 (m, 1 H), 6.65 (br s, 1 H) , 5.99 (m, 1H), 5.40-5.10 (m, 4H), 4.52 (m, 3H), 4.06 (m, 1H), 3.79 (m, 1H), 3.34 (m, 1H), 2.97 (s, 3H) ), 2.90-2.60 (m, 5H), 2.50-2.40 (br s, 1H), 1.80-1.20 (m, 10H). Preparation of Example AS Scheme 36 AS I. DIPEA, CH2CI2; II. LiOH, THF / HzO; III. Compound 8, HOBt, EDC, DIPEA, THF. Compound 85a Compound 85a was prepared following the same procedure as for Example 4, except that 4-chloro-methyl-thiazole (purchased from TCI America) was used in place of Compound 3, and methyl amine was used instead of isopropyl-amine. Compound 83 To Compound 85a (1.40 grams, 3.12 mmol) in CH 2 Cl 2 (9 milliliters) was added N, N-di-isopropyl-amine (1.04 milliliters, 5.85 mmol), followed by Compound 5 (280 microliters, 1.95 mmol). . The reaction mixture was stirred for 3.5 hours at 25 ° C. The solvent was removed under reduced pressure. Purification by Combi-Flash® (stationary phase: silica gel; eluent: gradient from 90 to 100 percent EtOAc / hexane) gave Compound 83 (0.51 grams), m / z: 286.0 (M + H) +. Compound 84 Compound 83 (0.51 grams, 1.77 millimoles) was dissolved in tetrahydrofuran (10 mmol), and aqueous 1M LiOH (3.54 milliliters) was added. The mixture was stirred at 25 ° C for 2 hours. The reaction was quenched with 1M HCl (4.8 milliliters), and the mixture was adjusted to a pH of 2. The mixture was extracted with ethyl acetate. The organic layers were dried over Na 2 SO 4 > they were filtered, and evaporated, to provide Compound 84 (0.430 grams). This material was used in the next step without further purification, m / z: 272.0 (M + H) +. Example AS Compound 84 (150 milligrams, 0.55 millimole) was dissolved in tetrahydrofuran (7.15 mmol). Compound 8 (225 milligrams, 0.55 millimoles) was added, followed by HOBt (112 milligrams, 0.83 millimoles), iPr2NEt (393 microliters, 2.20 millimoles), and EDC (198 microliters, 1.11 millimoles). The mixture was stirred at 25 ° C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted in ethyl acetate, and washed sequentially with saturated aqueous Na 2 CO 3, water, and brine. The organic phase was dried over Na2SO4 filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel; eluent: 7 percent i-PrOH / CH2Cl2) gave Example AS (219 milligrams, 60 percent), m / z: 663.1 (M + H) +. 1 H NMR (CDCl 3) d 8.87 (s, 1H); 8.76 (s, 1H); 7.84 (s, 1H); 7.40-7.00 (m, 10H); 6.22 (br s, 1H); 5.73 (br s, 1H); 5.22 (m, 2H); 4.50 (m, 2H); 4.16 (br s, 1H); 4.05 (br s, 1H); 3.75 (m, 1H); 2.93 (s, 3H); 2.90-2.60 (m, 5H); 2.90 (m, 1H); 2.31 (m, 1H); 1.60-1.30 (m, 4H); 1.00-0.80 (m, 6H). Preparation of Example AT Scheme 37 I. DIPEA, CH2Cl2; II. LiOH, THF / H20; III. Compound 8, HOBt, EDC, DIPEA, THF. Compound 87 Compound 87 (386 milligrams) was prepared from Compound 86, following the same procedure used to prepare Compound 7 from Compound 6, except that Compound 68 was used in place of Compound 4. m / z: 286.0 (M + H) +. Preparation of Example AU Scheme 38 AU I. DIPEA, CH2Cl2; II. LiOH, THF / H20; III. Compound 8, HOBt, EDC, DIPEA, THF. Compound 85b Compound 85b following the same procedure for Compound 4, except that 4-chloro-methyl-thiazole (obtained in TCI America) was used in place of Compound 3. Compound 88 Compound 88 (341 milligrams) was prepared following the same procedure used to prepare the Compound 83, with the exception that Compound 85b (300 milligrams, 1.95 millimoles) was used in place of Compound 68. m / z 312.0 (M + H) +. Compound 89 Compound 89 (341 milligrams) was prepared following the same procedure as for 84, with the exception that Compound 88 (293 milligrams, 0.99 millimole) was used instead of Compound 83. m / z 298.0 (M + H) +.
AU Example Au Example (226 milligrams, 64 percent) was prepared following the same procedure used to prepare AS, with the exception that Compound 89 (150 milligrams, 0.51 millimoles) was used instead of Compound 84. m / z 689.1 (M + H) +. 1 H NMR (CDCl 3) d 8.87 (s, 1H); 8.74 (s, 1H); 7.83 (s, 1H); 7.40-7.00 (m, 10H); 6.21 (m, 1H); 5.73 (m, 1H); 5.29 (m, 1H); 5.17 (m, 2H); 4.88 (d, J = 16 Hz, 1H); 4.47 (d, J = 16 Hz, 1H); 4.18 (m, 1H); 3.75 (br s, 1H); 2.90-2.60 (m, 6H); 2.51 (br s, 1H); 2.31 (m, 1H); 1.60-1.30 (m, 4H); 1.00-0.80 (m, 10H). Preparation of Example AV Scheme 39 I. DIPEA, CH2Cl2; II. LiOH, THF / HzO; III. Compound 8, HOBt, EDC, DIPEA, THF. Compound 90 Compound 90 (190 milligrams) was prepared following the procedure used to prepare Compound 4, except that 4-chloro-methyl-2-methyl-thiazole was used in place of Compound 3. m / z: 141.1 (M + H) +. Compound 91 Compound 91 (400 milligrams) was prepared following the procedure used to prepare Compound 6, except that Compound 90 was used in place of Compound 4. m / z: 300.0 (M + H) +. Compound 92 Compound 92 (188 milligrams) was prepared following the procedure used to prepare Compound 7, except that Compound 91 was used in place of Compound 6. m / z: 284.0 (MH) | Example AV Example AV ( 107 milligrams) was prepared following the procedure used to prepare Compound C, except that Compound 92 was used in place of Compound 7. 1 H NMR (CDCl 3) d 8.76 (s, 1 H), 7.78 (s, 1 H), 7.27- 7.07 (m, 10H), 6.93 (s, 1H), 6.25 (m, 2H), 5.39 (m, 1H), 5.19 (m, 2H), 4.37-4.32 (m, 2H), 4.06 (m, 1H) , 3.81 (br s, 1H), 2.83 (m, 4H), 2.65 (br s, 7H), 2.28-2.22 (m, 1H), 1.51-1.37 (m, 4H), 0.82 (m, 6H): m / z 677.2 (M + H) +. Preparation of Example AW Scheme 40 I. SOCI2 / MeOH; II. DIPEA, CH2CI2; III. LiOH, THF / H20; IV. Compound 8, HOBt, EDC, IPEA, THF. Compound 93 Compound 93 is commercially available in TCI, and was used without further purification. Compound 94 To a solution of Compound 93 (500 milligrams, 6.76 mmol) in methanol (20 milliliters) was added dropwise thionyl chloride (0.5 milliliters, 6.6 millimoles). The mixture was stirred at 60 ° C for 20 minutes, and concentrated in vacuo, to give Compound 94. Compound 95 To a stirred solution of Compound 94 (3.7 mmol) and di-isopropyl-ethyl-amine (1.4 milliliters, 8.3 millimoles) in dichloromethane (50 milliliters), CDI (609 milligrams, 3.7 millimoles) was added. The mixture was stirred for 12 hours. Compound 9 was added, and the mixture was stirred for an additional 12 hours. Concentration and purification by column chromatography by evaporation Instantaneous (from 0 to 100 percent EtOAc / hexane) gave Compound 95 (100 milligrams), m / z: 344.3 (M + H) +. Compound 96 Compound 96 (39 milligrams) was prepared following the same procedure used to prepare Compound 7, except that Compound 95 was used in place of Compound 6. m / z: 328.3 (M + H) +. Example AW Example AW (107 milligrams) was prepared following the procedure for Example C, except that Compound 96 was used in place of Compound 7. 1H RN (CDCI3) d 8.79 (s, 1 H), 7.82 (s, 1 H), 7.27-7.09 (m, 10 H), 6.95 (s, 1H), 6.23 (m, 1 H), 6.14 (s, 1 H), 5.22 (s, 3 H), 4.45 (m, 2 H), 4.35-4.0 (m, 3 H), 3.8 (m, 1 H), 3.6 (m, 1 H), 3.25 (s, 3 H), 3.21 (m, 2 H), 2.95 (s, 3 H) , 2.8-2.6 (m, 4 H), 2.0-1.4 (m, 4 H), 1.25 (m, 4 H), 1.05 (m, 4 H): m / z 721.3 (+ H) +. Preparation of Examples AX and AY Scheme 41 I. DMSO, Et3N, S03 pyridine: II. NaBH (OAc) 3, AcOH, methyl-amine / MeOH.
Example AX To a solution of Example I (650 milligrams, 1.00 millimoles) in dimethyl sulfoxide (3.5 milliliters), triethylamine (0.5 milliliters) was added. The mixture was stirred for 30 minutes. Pyridine-S03 was added to the mixture, and then stirred for 60 minutes. The mixture was poured into ice water, and then stirred for 30 minutes. The mixture was diluted with EtOAc and water, saturated NaHCO3, and brine. The concentration gave Example AX. m / z: 705.2 (M + H) +.
Example AY To a stirred solution of Example AX (70 milligrams, 0.099 mmol) and methyl-amine (1.5 milliliters, 2M) in MeOH (1.5 milliliters), AcOH (119 milligrams, 1.99 millimoles) was added. The mixture was stirred for 2 hours. NaBH / (OAc) 3 (94 milligrams) was added, and the mixture was stirred for 2 hours. Concentration and purification by HPLC preparation gave Example AY (30 milligrams). 1 H NMR (CDCl 3) d 8.79 (s, 1 H), 7.82 (s, 1 H), 7.27-7.09 (m, 10 H), 6.95 (s, 1 H), 6.23 (m, 1 H), 6.14 (s, 1 H), 5.22 (s, 2 H), 4.45 (m, 1 H), 4.35-4.0 (m, 4 H), 3.8 (m, 1 H), 3.6 (m, 1 H), 3.21 (m, 1 H), 2.95 (s, 3 H), 2.93 (s, 3H), 2.8-2.6 (m, 4 H), 2.0-1.4 (m, 4 H), 1.25 (m, 4 H), 1.05 (m, 4H): m / z 720.3 (M + H) +.
Preparation of Example AZ Scheme 42 AZ I. HOBt, EDC, DIPEA, THF. Example AZ Compound AZ (61 milligrams) was prepared following the procedure for Example C, except that Compound 87 was used in place of Compound 7, and that Compound 79 was used in place of Compound 8. 1 H NMR (CDCl 3 ) d 8.77 (s, 1H), 8.72 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 6.23 (d, 1H), 5.28-5.24 (m, 2H), 4.85 (d, 1H), 4.71-4.57 (m, 2H), 4.08-4.03 (m, 1H), 3.78 (br s, 1H), 3.51 (br s, 1H), 2.87 (s, 3H), 2.33 (br s, 1H ), 2.13-2.06 (m, 1H), 1.49-1.33 (m, 8H), 0.93-0.80 (m, 12 H): m / z 539.2 (M + H) +. Preparation of Examples BA and BB Scheme 43 i. to. CDI / ¡Pr2NEt; b. Compound 9; II. to. NaOH / THF / H20; b. HCI; III. Compound 8 / EDC / HOBt, IPEA, THF; IV. Et3SiH, TFA.
Compound 97 Compound 97 is commercially available in TCl, and was used as received. Compound 98 To a stirred solution of Compound 97 (1 gram, 2.2 mmol) and di-isopropyl-ethyl-amine (1.6 milliliters, 8.9 mmol) in dichloromethane (26 milliliters), CDI (362 milligrams, 2.2 mmol) was added. ). The mixture was stirred for 12 hours. Compound 9 was added, and the mixture was stirred for an additional 12 hours. Concentration and purification by flash column chromatography (0 to 8 percent: MeOH / DCM) gave Compound 98 (1.2 grams), m / z 608.1 (M + H) +.
Compound 99 Compound 99 (1.2 grams) was prepared following the same procedure used to prepare Compound 67, with the exception that Compound 98 was used in place of Compound 66. m / z 592.2 (+ H) +. Example BA Example BA (111 milligrams) was prepared following the procedure used to prepare Example C, except that Compound 99 was used in place of Compound 7. m / z 986.1 (M + H) +. Example BB To a stirred solution of Example BA (111 milligrams, 0.113 millimoles) and trifluoroacetic acid (1.4 milliliters), Et3H (0.1 milliliters) was added. The mixture was stirred for 60 minutes, then concentrated and partitioned with EtOAc and saturated NaHCO 3, followed by extraction with EtOAc (twice), and drying over Na 2 SO 4. Concentration and purification by flash column chromatography (0 to 15 percent: MeOH / DCM) gave Example BB (50 milligrams). 1 H-NMR (CDCl 3) d 8.75 (s, 1 H), 7.79 (s, 1 H), 7.42 (s, 1 H), 7.22-7.12 (m, 9H), 6.99-6.96 (m, 2H), 6.86. (s, 1H), 6.71 (m, 2H), 5.51 (br S, 1 H), 5.17 (m, 2H), 4.57-4.52 (m, 1 H), 4.39-4.35 (m, 2 H), 4.07 (m, 1 H), 3.74 (br s, 1 H), 3.28-3.19 (m, 1 H), 3.09-2.76 (m, 6 H), 3.65-2.58 (m, 3 H), 1.49 (m, 2 H), 1.36-1.20 (m, 8 H); m / z 743.2 (M + H) +.
Preparation of Example BC Scheme 44 BC I. HOBt, EDC, DIPEA, THF, Compound 29. Example BC Example BC (95 milligrams) was prepared following the procedure used to prepare Example C, except that Compound 29 was used instead of Compound 7, and that Compound 78 was used in place of Compound 8. H NMR (CDCl 3) d 8.75 (s, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 6.28 (d, 1H), 6.18 (m, 1H), 5.26-5.21 (m, 3H), 4.47-4.30 (m, 2H), 4.11-4.00 (m, 1H), 3.91 (br s, 1H), 3.59 (br s, 1H), 3.28 (m, 1H), 2.97-2.90 (m, 3H), 2.26-2.19 (m, 1H), 1.39-1.24 (m, 10H), 1.09-1.01 (m, 6 H), 0.94-0.86 (m, 6 H): m / z 553.1 (M + H) +. Preparation of Examples BD and BE Scheme 45 BE I. LiOH, THF / H20; H. Compound 78, HOBt, EDC, DIPEA, THF; III. to. TFA clean; b. NaOH, THF, HzO. Example BD Example BD (148 milligrams) was prepared following the procedure used to prepare Example C, except that Compound 13e was used in place of Compound 7, and that Compound 78 was used instead of amine 8. m / z 611.1 (M + H) +. Example BE Example BD (148 milligrams, 0.242 mmol) was dissolved in trifluoroacetic acid (3 milliliters), and allowed to stir at 25 ° C for 3 hours. The solvent was removed under reduced pressure, and the residue was diluted with tetrahydrofuran (3 milliliters), and 2N aqueous NaOH was added to a pH of 10. The mixture was allowed to stir for 20 minutes, and extracted with EtAOc. The organic layer was washed in sequence with water and brine, dried over MgSO4, filtered, and evaporated. Purification by flash chromatography (from 0 to 10 percent MeOH / CH2Cl2) gave Example BE (109 milligrams). 1 H NMR (CDCl 3) d 8.75 (s, 1 H), 7.80 (s, 1 H), 6.97-6.94 (d, 1 H), 6.90 (s, 1 H), 6.32 (br s, 1 H), 5.26-5.22 ( m, 2H), 5.12 (d, 1H), 4.51-4.39 (m, 3H), 4.25-4.22 (m, 2 H), 3.87 (br s, 1H), 3.62 (br s, 1 H), 3.27- 3.18 (m, 1 H), 2.94 (s, 3 H), 1. 41-1.31 (m, 10 H), 1.13-1.00 (m, 9 H). m / z: 555.1 (M + H) +. Preparation of Example BF Scheme 46 I. LiOH, THF / H20; II. Compound 8, HOBt, EDC, DIPEA, THF. Compound 100 Compound 100 was prepared using the same method used to prepare Compound 122, except that Compound 9 was replaced with Compound 68 (see Scheme 70). Compound 101 CompuestolOO (108 milligrams, 0.423 mmol) was dissolved in tetrahydrofuran (2 milliliters), and then 847 microliters of 1M LiOH / H20 was added. After stirring overnight, 843 microliters of 1N HCl was added. The concentration gave Compound 101. Example BF Example BF (24 milligrams) was prepared following the procedure used to prepare Example C, except that Compound 101 was used in place of Compound 7. 1 H NMR (CDCl 3) d 8.77 (s, 1?), 8.73 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.27-7.10 (m, 10H), 6.55-6.52 (d, 1H), 5.84 ( d, 1 H), 5.21-5.19 (m, 3 H), 4.77-4.53 (m, 2H), 4.39 (br s, 1 H), 4.11-3.99 (m, 2 H), 3.81 (br s, 1 H) ), 3.58 (m, 2 H), 2.86 (s, 3 H), 2.81-1.72 (m, 5H), 2.04 (m, 1 H), 1.85 (m, 1 H), 1.66-1.37 (m, 6) H): m / z 665.2 (M + H) +. Preparation of Example BG Scheme 47 I. Trifluoro-ethyl acetate, Mel, Cs2C03, THF. Example BG Example R (102 milligrams, 0.137 mmol) was dissolved in tetrahydrofuran (2 milliliters), and then 2 milliliters of ethyl trifluoroacetate were added. Then 1.3 equivalents of Mel and an excess of Cs2C03 were added. After stirring for 1 day, the mixture was partitioned with EtOAc and saturated Na 2 CO 3, extracted with EtOAc (twice), and dried over Na 2 SO 4. Purification by flash chromatography (0 to 20 percent MeOH / CH2Cl2) gave Example BG (6.5 milligrams). 1 H NMR (CD 3 OD) 69.94 (s, 1 H), 8.27 (s, 1 H), 7.73 (s, 1 H), 7.30-7.10 (m, 10H), 5.29, 5.17 (d, 2H), 4.72 (s, 3H), 4.29 (m, 1H), 4.15 (br, 1H), 3.83 (br s, 1H), 3.61 (m, 2H), 3.07 (s, 3H), 2.93 (m, 2H), 2.82-2.70 (m, 4H), 2.68-2.58 (m, 2H), 2.42 (s, 3H), 2.05 (m, 2H), 1.70-1.40 (m , 10H). m / z: 720.2 (M + H) +. Preparation of Example BH Scheme 48 I. Amine 59, HOBt, EDC, DIPEA, THF. Example BH Example BH (78 milligrams) was prepared following the procedure used to prepare Example C, except that Compound 87 was used in place of Compound 7, and that Compound 46 was used instead of Compound 8. 1H RN (CDCl 3) d 8.73 (s, 1H), 8.68 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.18-7.09 (m, 10H), 6.26 (m, 1H), 5.76 ( m, 1H), 5.22-5.18 (m, 4H), 4.71-4.65 (d, 1H), 4.46-4.40 (d, 1H), 4.11-4.04 (m, 2H), 3.81 (br s, 1H), 314 (br s, 1H), 2.83 (s, 3H), 2.76-2.52 (m, 4H), 1.88 (m, 1H), 1.51-1.37 (m, 2H), 0.73-0.69 (m, 6 H) m / z 663.2 (M + H) +. Preparation of Examples Bl and BJ Scheme 49 I. Compound 46 / EDC / HOBt, IPEA, THF; II. Et3SIH, TFA. EXAMPLE Bl Example Bl (1.78 grams) was prepared following the procedure used to prepare Example C, except that Compound 99 was used in place of Compound 7, and that Compound 46 was used in place of Compound 8. m / z 986.1 (M + H) +. Example BJ Example BJ (728 milligrams) was prepared following the procedure used to prepare Example BB, except that Example Bl was used in place of Example BA. 1 H-NMR (CDCl 3) d 8.75 (s, 1 H), 7.79 (s, 1 H), 7.42 (s, 1 H), 7.22-7.12 (m, 9H), 6.99-6.96 (m, 2H), 6.86 (s, 1H), 6.71 (m, 2H), 5.51 (br s, 1 H), 5.17 (m, 2H), 4.57-4.52 (m, 1 H), 4.39-4.35 (m, 2 H), 4.07 (m, 1 H), 3.74 (br s 1 H), 3.28-3.19 (m, 1 H), 3.09-2.76 (m, 6 H), 3.65-2.58 (m, 3 H), 1.49 (m, 2 H), 1.36-1.20 (m, 8 H); m / z 743.2 (M + H) + Preparation of Compounds 104-115 Scheme 50 102 103 104 I. a. CDI, DIPEA, MeCN; b. Compound 9, MeCN. II. 1M LiOH, THF.
Compound 102 Compound 102 is commercially available from Aldrich Chemical Co., and was used without further purification. Compound 103 Compound 102 (5.5 mmol) was suspended in MeCN (55 milliliters), and DIPEA (8.25 mmol) was added. The carbonyl-di-imidazole (5.5 mmol) was diluted in MeCN (20 milliliters), and the solution was slowly added to the reaction mixture for 45 minutes. The resulting mixture was allowed to age overnight. Compound 9 (5.5 mmol) was diluted in MeCN (10 milliliters), and treated with DIPEA (5.25 mmol) before being added to the reaction mixture, which was then allowed to age overnight. The volatiles were removed in vacuo, and the residue was taken up in EtOAc (50 milliliters), and washed with 1M HCl (50 milliliters). The layers were separated, and the aqueous layer was extracted with EtOAc (50 milliliters, three times). The combined organic layers were washed with saturated Na 2 CO 3 until the pH of the washings was approximately pH 8. A wash with brine (30 milliliters) was followed by drying over anhydrous MgSO 4. Following the vacuum concentration, the residue was purified on Si02 (0 to 65 percent EtOAc / exas), to provide 0.340 grams (20 percent) of Compound 3, as an amorphous white solid (m / z 314.0 (M + H) +. Compound 103 (1.1 mmol) was diluted in tetrahydrofuran (5 milliliters), and treated with freshly prepared 1M LiOH (2.2 millimoles). The biphasic reaction was vigorously stirred for 2 hours before quenching with 1 M HCl (3 mmol). The reaction was extracted with EtOAc (15 milliliters, five times), and the combined organics were washed with brine (30 milliliters), dried over anhydrous Na 2 SO 4, and concentrated to provide 0.282 grams (86 percent) of Compound 104, as a white amorphous powder, which was used without further purification. H-NMR (CDCl 3, 300 MHz): 7.06 (s, 1H); 4.37 (s, 1H); 3.28 (p, J = 6.9 Hz, 1H); 3.00 (s, 3H); 1.62 (s, 6H); 1.39 (d, J = 6.9 Hz, 6H). Scheme 51 107 108 I. HCl, MeOH; II. to. CDI, DIPEA, MeCN; b. Compound 9, MeCN. III. 1M LiOH, THF.
Compound 105 Compound 105 is commercially available from Aldrich Chemical Co., and was used without further purification. Compound 106 Compound race 105 (12.2 mmol) was diluted in MeOH (100 milliliters). A solution of HCI / dioxane (4, 25 mmol), and the solution was refluxed overnight. The volatiles were removed in vacuo to yield 2.60 grams (97 percent) of Compound 106 as a racemic mixture. The white foamy solid was used without further purification (m / z 147.0 (+ H) +) Compound 107 Compound 106 (5 mmol) was diluted in MeCN (65 milliliters), and treated with DIPEA (25 mmol). The resulting solution was added slowly through an addition funnel to a solution of CDI (5 mmol) in MeCN (30 milliliters), and allowed to age overnight, Compound 9 (5 mmol) and DIPEA (3 mmol) were added to the solution. The reaction solution, which was allowed to age overnight, was removed in vacuo, and the residue was taken up in EtOAc and saturated Na 2 CO 3 (30 milliliters each) The aqueous layer was extracted with EtOAc (25 milliliters, three times), and the combined organics were washed with brine (50 milliliters), and dried over anhydrous MgSO 4, followed by concentration in vacuo, purification by column chromatography on SiO2 (from 0 to 10 percent MeOH). DCM) provided 0.36 grams (21 percent) of the Com racemic position 107 as a yellow oil (m / z 343.1 (M + H) +). Compound 108 Compound 107 (1.05 mmol) was taken up in tetrahydrofuran (5 milliliters), and treated with a freshly prepared solution of 1 M LiOH (2.1 mmol). The solution was stirred vigorously for 2 hours, and quenched with 1 M HCl (2.1 mmol). The volatiles were removed in vacuo, and the resulting oil was azeotropically distilled with toluene, until a quantitative yield of racemic Compound 107 was produced, as an amorphous white solid, which was used without further purification (m / z 329.1 (M + H) +. Scheme 52 I. p-02NC6H40 (CO) CI, NMM, DCM, 0 ° C to room temperature; II. Compound 9, Et 3 N, DMAP, THF, 70 ° C; III. 1M LiOH, THF. Compound 109 Compound 109 is commercially available in Bachem, and was used as received.
Compound 110 Compound 109 (4.1 mmol) was diluted in dichloromethane (5 milliliters), and treated with N-methylmorpholine (8.2 mmol). This solution was added slowly to a solution in dichloromethane (5 milliliters) of 4-nitro-phenyl chloroformate (4.1 mmol) at 0 ° C. The reaction was then allowed to warm to room temperature overnight. The volatiles were removed, and the residue was taken up in saturated EtOAc 7 Na2CO3. The aqueous layer was extracted with EtOAc (10 milliliters, three times), and the combined organics were washed with brine (30 milliliters) before being dried over anhydrous Na2SO4. Following concentration in vacuo, the residue was purified by column chromatography on SiO2 (0 to 25 percent EtOAc / hexanes), to yield 0.75 grams (51 percent) of Compound 110 as an amorphous white solid (m / z 354.8 (M + H) + Compound 111 Compound 110 (1.1 mmol) was diluted in tetrahydrofuran (3.5 milliliters) Compound 9 (1.4 mmol) was diluted in tetrahydrofuran (3 milliliters), treated with Et3N (2.8 millimoles), and transferred to a solution to the reaction solution, DMAP (0.11 mmol) was added, and the reaction was heated at 70 ° C for 2 hours.After cooling to room temperature, EtOAc (10 milliliters) was added. ) and saturated Na 2 CO 3 The aqueous phase was extracted with EtOAc (10 milliliters, three times), and the combined organics were washed with saturated Na 2 CO 3, H 2 O, and brine (15 milliliters each) After drying over anhydrous MgSO 4, the volatile were removed in vacuo, and the residue was purified by column chromatography on Si02 (0 to 50 percent ethyl acetate / hexanes), to yield 0.346 grams (82 percent) of Compound 111 (m / z 386.0 (M + H) +). Compound 112 Compound 111 (0.88 mmol) was taken up in tetrahydrofuran (4 milliliters), and treated with freshly prepared 1M LiOH (1.8 mmol). The reaction mixture was stirred vigorously for 1.5 hours, and quenched with 1 M HCl (2.5 mmol). The reaction mixture was extracted with EtOAc (10 milliliters, three times), and the combined organics were washed with brine (30 milliliters), and dried over anhydrous Na2SO4. Concentration in vacuo yielded 0.300 grams (92 percent) of Compound 112, as a colorless film, which was used without further purification (m / z 372.0 (M + H) +). Scheme 53 113 114 115 I. T SCHN2, THF / MeOH; II. piperidine, DMF. Compound 113 Compound 113 is commercially available from Chem-Impex, and was used without further purification.
Compound 114 Compound 113 (3.2 mmol) was diluted in tetrahydrofuran (15 milliliters). TMSCHN2 (3.2 mmol) was added slowly, followed by MeOH (5 milliliters). The solution became rapidly colorless, and a heavy gas evolution was observed. After being left overnight, the volatiles were removed in vacuo, and the residue was purified by column chromatography on SiO2 (0 to 50 percent EtOAc / hexanes), to yield 0.805 grams (52 percent) of Compound 114 (m / z 505.2 (+ Na) +). Example 115 Compound 114 (1.7 mmol) was diluted in dimethylformamide (4 milliliters), and piperidine (1 milliliter) was added. After 30 minutes, the volatiles were removed in vacuo, and the residue was purified by column chromatography on SiO2 (0 to 5 percent MeOH / DCM), to provide 0.414 grams (94 percent) of Compound 115, as a white amorphous solid (m / z 261.0 (M + H) +). Preparation of Example BK Scheme 54 I. Compound 29 / EDC / HOBt / DIPEA / THF.
Compound BK Compound 79 (0.70 mmol) and Compound 29 (0.91 mmol) were combined in tetrahydrofuran (7 milliliters). HOBt (0.91 millimoles), DIPEA (1.05 millimoles), and EDC (0.91 millimoles) were added consecutively at room temperature, and the reaction was allowed to age overnight. The volatiles were removed in vacuo, and the residue was taken up in 3/1 CHCl 3 / IPA and saturated Na 2 CO 3 (15 milliliters each). The aqueous layer was extracted with 3/1 CHCl 3 / IPA (10 milliliters, three times), and the combined organics were washed with saturated Na 2 CO 3, water, and brine (15 milliliters of each). Following drying over anhydrous gSO4, the volatiles were removed in vacuo, and the residue was purified by column chromatography on S02 (0 to 10 percent MeOH / DCM), to yield 8.5 milligrams (2 percent) of Compound BK. m / z 581.2 (M + H) +; 1 H NMR (CDCl 3, 300 MHz): 8.91 (s, 1 H); 7.89 (s, 1 H); 7.15 (s, 1 H); 6.52-6.0 (br m, 2H); 5.26 (s, 2H); 5.18 (br d, J = 8.1 Hz, 1 H); 4.55 (s, 2H); 4.06 (br s, 1 H); 3.79 (br s, 1 H); 3.48 (m, 2H); 3.09 (s, 3H, minor rotamer); 3.01 (s, 3H, major rotamer); 2.34 (m, 1 H); 1 .60-1 .30 (m, 8H); 1.42 (d, J = 6.9 Hz, 6H); 0.98 (t, J = 7.2 Hz, 6H); 0.86 (m, 6H). Preparing the Ejem plo B L Esq uema 55 I. Compound 8 / EDC / HOBt / DIPEA / THF. Example BL Example BL was prepared in a manner similar to Example BK, using Compound 104 (0.26 mmol) and Compound 8 (0.29 mmol) to yield 0.087 grams (64 percent) of Example BL, as an amorphous white solid, m / z 691.3 (+ H) +; 1 H NMR (CDCl 3, 300 MHz): 8.82 (s, 1 H), 7.82 (s, 1 H), 7.30-7.10 (m, 11 H), 7.06 (s, 1 H), 6.54 (d, J = 9.6 Hz, 1 H) , 5.89 (d, J = 8.4 Hz, 1H), 5.22 (s, 1H), 5.07 (s, 1H), 4.45 (AB d, J = 16.5 Hz, 1H), 4.37 (AB d, J = 15.6 Hz, 1H), 4.07 (m, 1H), 3.68 (m, 1H), 3.40 (m, 1H), 3.06 (s, 3H, minor rotamer), 2.89 (s, 3H, major rotamer), 2.90-2.54 (m, 4H), 1.60-1.25 (m, 16H). Preparation of Examples BMa and BMb Scheme 56 BMa and BMb I. Compound 8 / EDC / HOBt / DIPEA / THF.
Examples BMa and BMb Examples BMa and BMb were prepared in a manner similar to Compound BK, using Racemic Compound 108 (0.36 mmol) and Compound 8 (0.28 mmol). The enantiomeric products were separated by preparative HPLC (Chiralcel OD-H (250 x 4.6 millimeters, 70.30 Heptane / IPA, 30 minutes)), to yield 0.008 grams (4 percent) of the BMa enantiomer (HPLC RT = 11.71 minutes) m / z 720.3 (M + H) +; 1 H-NMR (CDCl 3, 300 MHz): 8.73 (s, 1H); 7.78 (s, 1H); 7.41 (br s, 1H); 7.30-7.00 (m, 11H); 6.94 (s, 1H); 5.40 (br s, 1H); 5.18 (br s, 2H); 4.56 (AB d, J = 15 Hz, 1H); 4.48 (AB d, J = 16 Hz, 1H); 4.39 (br s, 1H); 4.05 (br s, 1H); 3.73 (br s, 1H); 3.25 (s, 3H, minor rotamer); 3.23 (m, 1H); 2.98 (s, 3H, major rotamer); 2.82-2.30 (m, 10H); 1.60-1.20 (m, 6H); 1.32 (d, J = 7 Hz, 6H) and 0.010 grams (5 percent) of the BMb enantiomer (HPLC 15.41 minutes), (m / z 720.3 (M + H) +, 1 H-NMR (CDCI3, 300 MHz) : 8.78 (s, 1H), 7.83 (s, 1H), 7.38 (br d, J = 8 Hz, 1H), 7.30-7.05 (m, 11H), 7.02 (s, 1H), 5.52 (d, J = 9 Hz, 1H), 5.25 (AB d, J = 13 Hz, 1H), 5.21 (AB d, J = 13 Hz, 1H), 4.85-4.62 (m, 2H), 4.44 (d, J = 16 Hz, 1H), 3.99 (br s, 1H), 3.78 (br s, 1H), 3.37 (br s, 3H, minor rotamer), 3.26 (m, 1H), 3.07 (s, 3H, major rotamer), 2.77 (s) , 6H), 2.86-2.60 (m, 4H), 1.6-1.3 (m, 6H), 1.35 (d, J = 7 Hz, 6H) Preparation of Examples BN and BO Scheme 57 BN (R -Bu) BO (R = H) I. Compound 8 / EDC / HOBt / DIPEA / THF; II. TFA, 1M NaOH. Example BN Example BN was prepared in a manner similar to Example BK, using Compound 112 (0.78 mmol) and Compound 8 (0.60 mmol), to yield 0.227 grams (50 percent) of Compound BN, as a colorless film, (m / z 763.3 (M + H) +). Example BO Example BO was prepared in a manner similar to Example A, using Example BN (0.29 mmol) to yield 0.149 grams (72 percent) of Example BO, as an amorphous white solid, (m / z 707.3 (M + H) +); 1 H NMR (CDCl 3, 300 MHz): 8.82 (s, 1H); 7.84 (s, 1H); 7.26-7.03 (m, 11H); 6.99 (s, 1H); 6.69 (d, J = 9.6, 1H); 6.42 (br s, 1H); 5.47 (br d, J = 8.7 Hz, 1H); 5.27 (AB d, J = 13 Hz, 1H); 5.22 (AB d, J = 13 Hz, 1H); 4.55 (AB d, J = 16 Hz, 1H); 4.43 (AB d, J = 16 Hz, 1H); 4.18 (m, 1H); 4.00 (m, 2H); 3.72 (br s, 1H); 2.25 (m, 1H); 2.99 (s, 3H); 2.84-2.60 (m, 3H); 2.54-2.42 (m, 1H); 1.64-1.12 (m, 4H); 1.37 (d, J = 7 Hz, 6H); 1.11 (d, J = 6 Hz, 3H). Preparation of Examples BP-BR Scheme 58 I. Compound 78 / EDC / HOBt / DIPEA / THF; II.4M HCI / dioxane; III. HCHO, NaHB (OAc) 3l MeOH. Example BP Example BP was prepared in a manner similar to Example BK, using Compound 52 (0.22 millimoles) and Compound 78 (0.20 millimoies), to yield 0.091 grams (71 percent) of Example BP, as a colorless film ( m / z 654.2 (M + H) +). Example BQ Example BQ (0.14 millimoles) was treated with 4N HCl in dioxane (2 milliliters), to produce a white precipitate within 5 minutes. The solvents were removed, and the solid was absorbed in MeOH. Vacuum concentration provided 0.083 grams (99 per 100) of the HCl salt of Example BQ, as a colorless film (m / z 554.1 (+ H) +; 1 H-NMR (CD3OD, 300 MHz): 10.03 (s, 1H); 8.41 (s, 1H); 7.81 (s, 1H), 5.48 (s, 2H, minor rotamer), 5.35 (s, 2H, major rotamer), 4.74 (s, 2H), 4.34 (br s, 1H), 3.90 (br s, 1H); 3.78-3.54 (m, 2H), 3.20-2.98 (m, 5H), 2.20 (br s, 1H), 2.07 (br s, 1H), 1.60-1.4 (m, 10H), 1.12 (m, 6H). Example BR Example BQ (0.11 mmol) was absorbed in MeOH (1.5 milliliters), formaldehyde was added (37% in H20, 13.4 mmol), and aged for 10 minutes, NaHB (OAc) 3 (0.324 mmol) was added. ), and the reaction mixture was left to age at room temperature overnight More formaldehyde (13.4 millimoles) and NaHB (OAc) 3 (0.324 millimoles) were added, and they were left to age for an additional 6 hours at room temperature. were removed under vacuum, and the product was isolated by HPLC preparation, to yield 0.058 grams (77 percent) of the trifluorinated acid salt o-acetic of Example BR, as an amorphous solid, m / z 582.3 (+ H) +; 1 H-R N (CD3OD, 300 MHz): 9.07 (s, 1IH); 7.91 (s, IH); 7.25 (s, 1H); 5.47 (s, 2H, minor rotamer); 5.28 (s, 2H, major rotamer); 4.59 (AB d, J = 16 Hz, 1H); 4.53 (AB d, J = 16 Hz, 1H); 4.31 (dd, J = 9.2, 5 Hz, 1H); 3.88 (m, 1H); 3.59 (m, 1H); 3.32 (m, 1H); 3.20 (m, 2H); 2.98 (s, 3H); 2.89 (br s, 6H); 2.23 (m, 1H); 2.00 (m, 1H); 1.44 (m, 4H); 1.37 (d, J = 7 Hz, 6H); 1.10 (m, 6H). Preparation of Examples BS and BT Scheme 59 BS (R = t-Bu) BT (R ° H) I. Compound 8 / EDC / HOBt / DIPEA / THF; II. TFA, 1M NaOH. Compound 116 Compound 116 was prepared in a manner similar to Compound 75, using Compound 4 (0.76 mmol) and Compound 47 (0.64 mmol), to yield 0.218 grams (90 percent) of Compound 116, as a white foamy solid (m / z 384.1 (M + H) +). Example BS Example BS was prepared in a manner similar to Example BK, using Compound 116 (0.28 millimole) and Compound 8 (0.25 millimole), to yield 0.139 grams (72 percent) of Example BS, as a colorless film ( m / z 775.3 (M + H) +). Example BT Example BT was prepared in a manner similar to Example AM, using Example BU (0.18 mmol), to yield 0.080 grams (62 percent) of Example BT, as an amorphous white solid, m / z 719.3 (M + H) +; 1 H NMR (CDCl 3, 300 MHz): 8.79 (s, 1 H), 7.82 (s, 1 H), 7.27-7.0 (m, 10 H), 6.98-6.82 (m, 1 H), 6.85 (s, 1 H), 6.44 ( br s, 1H), 5.30 (s, 2H, minor rotamer), 5.22 (s, 2H, major rotamer), 5.04 (br s, 1H), 4.62 (AB d, J = 15 Hz, 1H), 4.54 (AB d, J = 15 Hz, 1H), 4.27 (br s, 1H), 4.11 (br s, 1H), 3.97 (br d, J = 10 Hz, 1H), 3.82 (br s, 1H), 3.57 (br s, 1H), 3.40-3.10 (m, 2H), 2.80-2.60 (m, 4H), 2.55 (m, 1H); 1.54 (m, 2H); 1.46-1.30 (m, 2H); 1.35 (d, J = 7 Hz, 6H); 0.94-0.72 (m, 4H). Preparation of Examples BU and BV Scheme 60 I. Compound 8 / EDC / HOBt / DIPEA / THF; II. TFA, 1M NaOH. Compound 117 Compound 117 was prepared in a manner similar to Compound 13d, except that Compound 4 was used 81.5 millimoles) and the L-enantiomer of Compound 10d (1.15 millimoles), to finally yield 0.328 grams (88 percent) of the Compound 190, as a white foamy solid (m / z 398.1 (M + H) +). Example BU Example BU was prepared in a similar manner to Example AL, using Compound 127 (0.33 millimole) and Compound 8 (0.30 millimole), to yield 0.196 grams (74 percent) of Example BU, as a white amorphous solid (m / z 789.3 (M + H) +). Example BV Example BV was prepared in a manner similar to Example AM, using Example BU (0.29 mmol), to yield 0.140 grams (77 percent) of Example BV, as an amorphous white solid, m / z 733.3 (M + H) +; 1 H NMR (CDCl 3, 300 MHz): 8.80 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, 10H); 6.70-6.10 (m, 1H); 6.86 (s, 1H); 6.20 (br d, J = 7 Hz, 1H); 5.24 (s, 2H); 4.81 (br d, J = 7 Hz, 1H); 4.82 (s, 2H); 4.34 (br d, J = 7 Hz, 1H); 4.16 (br s, 1H); 4.07 (br d, J = 6 Hz, 1H); 3.86 (br s, 1H); 3.38 (br s, 1H); 2.69 (m, 6H); 1.62-1.50 (m, 2H); 1.50-1.34 (n, 2H); 1.38 (m, 6H); 1.13 (d, J = 6 Hz, 3H); 0.98-0.76 (m, 4H). Preparation of Examples BW and BX I. Compound 75 / EDC / HOBt / DIPEA / THF; II. TFA, 1 NaOH. Example BW Example BW was prepared in a similar manner to Example BK, using Compound 75 (0.27 mmol) and Compound 46 (0.24 mmol), to provide 0.154 grams (86 percent) of Example BW, as an amorphous white solid (m / z 733.3 (M + H) +). Example BX Example BX was prepared in a manner similar to Example AM, using Example BW (0.21 mmol), to provide 0.091 grams (98 percent) of the trifluoroacetic acid salt of Example BX, as a white amorphous solid , m / z 677.5 (M + H) +; 1 H-NMR (CDCl 3, 300 MHz): 8.83 (s, 1H); 8.77 (s, 1H); 7.84 (s, 1H); 7.77 (s, 1H); 7.27-7.00 (m, 10H); 6.62 (d, J = 9 Hz, 1H); 6.44 (d, J - 6 Hz, 1H); 5.35 (d, J = 10 Hz, 1H); 5.24 (s, 2H); 4.69 (AB d, J = 15 Hz, 1H); 4.62 (AB d, J = 16 Hz, 1H); 4.14 (br m, 2H); 3.96-3.78 (m, 2H); 3.51 (dd, J = 11, 4.5 Hz, 1H); 3.38 (br s, 1H); 2.82-2.58 (m, 4H); 2.41 (m, 1H); 1.70-1.24 (m, 4H); 1.20-0.88 (m, 2H); 0.88-0.54 (m, 2H). Preparation of Examples BY and BZ Scheme 62 R, < - Boc, R¡¡ »H) 11 C ^ L BY (BZ { R, = R2 = &H) I. Compound 8 / EDC / HOBt / DIPEA / THF; II'.4M HCI / dioxane. Compound 118 Compound 118 was prepared in a similar manner to Compound 104, except that Compound 115 (40 mmol) was used in place of Compound 102, which was reacted with Compound 9 (0.48 mmol), to finally give 0.075. grams (89 percent) of Compound 118, as a white foamy solid (m / z 443.4 (M + H) +). Example BY Example BY was prepared in a manner similar to Example BM, using Compound 118 (0.17 mmol) and Compound 8 (0.15 mmol), to yield 0.079 grams (62 percent) of Example BY, as an amorphous white solid (m / z 834.3 (M + H) +). Example BZ Example BZ was prepared in a manner similar to Example BQ, using Example BY (0.095 mmol), to provide 0.082 grams (99 percent) of the HCI salt of Example BZ, as an amorphous white solid, m / z 734.2 (M + H) +; 1 H NMR (DMSO-d 6, 300 MHz): 8.08 (s, 1 H), 7.86 (br m, 3 H), 7.58 (d, J = 9 Hz, 1 H), 7.25-7.00 (m, 11 H), 6.32 (br s, 1H), 5.16 (s, 2H), 4.99 (br m, 4H), 4.48 (AB d, J = 15 Hz, 1H), 4.43 (AB d, J = 15 Hz, 1H), 4.02 (m, 1H), 3.89 (m, 1H), 3.63 (m, 1H), 3.22 (hep, J = 7 Hz, 1H), 2.87 (s, 3H), 2.76-2.56 (m, 4H), 1.58-1.15 (m , 10H), 1.29 (d, J = 7 Hz, 6H). Preparation of Example CA Scheme 63 CA I. 4-MorfoMn-carbonyl chloride, DIPEA, DCM. Example CA Example R (0.11 mmol) was diluted in dichloromethane (1 milliliter), and treated with 4-morpholine-carbonyl chloride (0.13 millimole) and DIPEA (0.16 millimole). After 2 hours, the volatiles were removed in vacuo, and the residue was purified by column chromatography on Si02 (0 to 20 percent MeOH / DCM), to provide 0.068 grams (76 percent) of Example CA, as an amorphous white solid, m / z 819.1 (M + H) +; H-NMR (CDCl 3, 300 MHz): 8.82 (s, 1H); 7.85 (s, 1H); 7.27-7.07 (m, 12H); 6.94 (s, 1H); 6.26 (br s, 1H); 5.73 (d, J = 8 Hz, 1H); 5.28 (AB d, J = 13 Hz, 1H); 5.22 (AB d, J = 13 Hz, 1H); 4.50 (AB d, J = 16 Hz, 1H); 4.44 (AB d, J = 16 Hz, 1H); 4.17 (m, 1H); 3.98 (br s, 1H) 3.76 (br s, 1H); 3.68 (br s, 1H); 3.60 (m, 4H); 3.40 (m, 2H), 3.32 (m, 4H); 2.97 (s, 3H); 2.87 (dd, J = 13, 5 Hz, 2H); 2.73, (m, 2H); 2.57 (m, 2H); 1.79 (m, 2H); 1.60-1.20 (m, 6H); 1.37 (d, J = 7 Hz, 6H). Preparation of Compound CB Scheme 64 I. Morpholine, EDC, HOBt, THF. Example CB Example CF (0.15 millimoles) was diluted in tetrahydrofuran (1 milliliter), and treated with morpholine (0.61 millimoles), HOBt (0.18 millimoles), and finally EDC (0.18 millimoles). The reaction mixture was allowed to age overnight. Then the reaction mixture was diluted in EtOAc and saturated Na 2 CO 3. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO 4, and concentrated in vacuo. The resulting residue was purified by preparative HPLC, to provide 0.024 grams (20 percent) of Example CB, as an amorphous white solid, m / z 790.4 (M + H) +; 1 H NMR (CDCl 3, 300 MHz): 8.81 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, 10H); 6.96 (s, 1H); 6.78 (d, J = 8 Hz, 1H); 6.67 (s, 1H); 5.36 (d, J = 9 Hz, 1H); 5.27 (AB d, J = 13 Hz, 1H); 5.20 (AB d, J = 13 Hz, 1H); 4.59 (s, 1H); 4.51 (s, 2H); 4.02 (m, 1H); 3.80-3.30 (m, 10H); 2.98 (s, 3H); 2.90-2.45 (m, 6H); 1.52 (m, 2H); 1.39 (d, J = 7 Hz, 6H); 1.32 (m, 2H). Preparation of Compound CC Scheme 65 DC I. N-methyl-piperazine, EDC, HOBt, DIPEA, THF. Example CC Example CC was prepared in a similar manner to Example CB, except that N-methyl-piperazine (0.16 mmol) was reacted with Compound AF (0.10 mmol), instead of morpholine, and added DIPEA (0.19 millimoles) to yield 0.009 grams (11 percent) of Example CC, as an amorphous white solid, m / z 803.4 (M + H) +; 1 H NMR (CDCl 3, 300 MHz): 8.80 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, 11H); 6.91 (s, 1H); 6.78 (m, 2H); 5.27 (AB d, J = 13 Hz, 1H); 5.21 (AB d; J = 13 Hz, 1H); 4.59 (m, 1H); 4.49 (AB d, J = 16 Hz, 4.44 (AB d, J = 16 Hz, 1H), 4.01 (m, 1H), 3.90-3.40 (m, 4H), 3.27 (hep, J = 7 Hz, 1H) 3.10-2.90 (m, 1H), 2.97 (s, 3H), 2.90-2.30 (m, 11H), 1.60-1.25 (m, 6H), 1.37 (d, J = 7 Hz, 6H). CP Scheme 66 I. HCHO / NaBH (OAc) 3 / eOH Example CP To a solution of Example R (30.5 milligrams, 0.043 mmol) in methanol (1.5 milliliters), formaldehyde (1 milliliter, 37 percent in H20) was added. After stirring for 10 minutes, NaBH (OAc) 3 (49 milligrams, 0.23 mmol) was added, and the resulting mixture was stirred for 10 hours. The reaction monitored with LC / MS. When the LC / MS indicated the absence of the starting material of Example R, the reaction mixture was evaporated to dryness, and filtered through a cotton plug. Then the crude product was purified through Combi-Flash (10 percent MeOH / CH2Cl2), to give 29.7 milligrams of Example CD. 1 H-NMR (CDCl 3, 500 MHz): 8.78 (s, 1 H), 7.83 (s, 1 H), 7.12-7.22 (m, 10 H), 6.85 (s, 1 H), 5.83 (d, 1 H, J = 8.5 Hz ), 5.23 (dAB, 2H, J = 13.1 Hz), 4.49 (CIAB, 2H, J = 16.5 Hz), 4.29 (m, 1H), 4.15 (m, 1H), 3.75 (m, 1H), 3.30 (m , 1H), 2.93 (s, 3H), 2.87 (dd, 1H, J1 = 5.5 Hz, J2 = 13.5 Hz); 2.72 (m, 2H), 2.66 (dd, J1 = 7.3 Hz, J2 = 13.3 Hz), 2.47 (br s, 1H), 2.36 (br s, 1H), 2.23 (s, 6H), 1.91 (m, 2H ), 1.56 (m, 2H), 1.40 (m, 2H), 1.40 (d, 6H, J = 6.8 Hz). m / z 734 (M + H) +, 756 (M + Na) +. Preparation of Example CE Scheme 67 I. EDC, HOBt, iPr2NEt, THF. II. to. HCI / dioxane; b. CDI, Pr2NEt, Compound 9, CH2Cl2. Compound 119 Compound 119 is commercially available from Aldrich, and was used as received.
Compound 120 A mixture of Compound 119 (200 milligrams, 0.91 millimole), Compound 8 (373.7 milligrams, 0.91 millimole), EDC (212 milligrams, 1.37 millimole), HOBt (160.3 milligrams, 1.19 millimole), and iPr2NEt (794.7 microliter, 4.56 mmol) in tetrahydrofuran was stirred for 10 hours at room temperature. The mixture was then evaporated to a small volume, and purified by Combi-Flash (eluted with 1 to 10 percent MeOH / CH 2 Cl 2). Fractions containing the target compounds were collected and re-purified by Combi-Flash (40 to 100 percent EtOAc / hexanes), to give 449 milligrams of Compound 120 as an oil, (m / z 611.0 (M + H) +). EC Example Compound 120 (449 milligrams, 0.74 millimole) was treated with HCI / dioxane (3 milliliters). The resulting mixture was evaporated to dryness, and lyophilized, to provide 373.6 milligrams of a white solid. To a solution of the above white compound (52.5 milligrams, 0.096 millimoles) in CH2Cl2 (10 milliliters), Compound 9 (19.8 milligrams, 0.096 millimoles), CDI (15.6 milligrams, 0.096 millimoles) was added, followed by iPr2NEt (33.4 microliters). , 0.192 millimoles). The mixture was stirred for 20 hours before evaporating to dryness. The mixture was added to CH2Cl2, and then filtered through a cotton plug. The filtrate was evaporated to dryness, and purified with Combi-Flash. The fractions with the Example CE was collected and re-purified on TLC, to give 15.1 milligrams of Example CE. 1 H-NMR (CDCl 3, 300 Hz): 8.79 (s, 1 H); 7.82 (s, 1H); 7.09-7.27 (m, 10H), 6.94 (s, 1H); 6.25 (d, 2H, J = 8.7 Hz); 5.23 (s, 2H); 5.17 (br s, 1H); 4.43 (dAB, 2H, J = 16.5 Hz); 4.29 (m, 1H); 4.13 (m, 1H), 3.76 (m, 2H); 3.48 (m, 1H); 3.29 (s, 3H); 3.25 (m, 1H), 2.94 (s, 3H), 2.65-2.82 (m, 4H), 1.75 (m, 2H), 1.54 (m, 2H), 1.39 (d, 5H, J = 6.9 Hz). m / z 707 (M + H) +; 729 (M + Na) \ Preparation of Example CF Scheme 68 Example CF Example CF was prepared using the same method as for Example CE, except that Compound 9 was replaced with Compound 68. H-R N (CDCl 3, 300 MHz): 8.79 (s, 1H); 8.74 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H); 7.12-7.27 (m, 10H); 6.15 (d, 1H, J = 8.7 Hz), 5.39 (d, 1H, J = 6.8 Hz), 5.21 (s, 2H), 5.06 (d, J = 9.1 Hz, 1H), 4.64 (dAB, 2H, J = 15.5 Hz), 4.28 (m, 1H), 4.134 (m, 1H), 3.79 (m, 1H), 3.70 (m, 1H), 3.34 (m, 1H), 3.28 (s, 3H), 2.87 (s) , 3H), 2.72 (m, 4H), 1.57 (m, 2H), 1.50 (m, 2H). (m / z 665.2 (M + H) +, 687.3 (M + Na) +. Preparation of Compound CG Scheme 69 I. a. CDI, DIPEA, MeCN; b. Compound 9, MeCN. II. 1 M LiOH, THF. III. EDCI HOBt, iPr2NEt, Compound 8. Compound 121 Compound 121 is commercially available from Aldrich, and was used as received. Compound 122 To a suspension of Compound 121 (2.05 grams, 11.3 mmol) in CH2Cl2 (40 milliliters), iPr2NEt (5.87 milliliters, 33.9 mmol) was added, followed by CDI (1.86 grams, 11.3 mmol). The resulting mixture was stirred at room temperature for 6 hours, and then Compound 9 (2.33 grams, 11.3 mmol) was added. The resulting mixture was stirred for another 10 hours, before evaporating to dryness. The mixture was redissolved in CH2Cl2, and the solid was removed by filtration. The filtrate was evaporated to dryness, and purified by Combi-Flash (eluted with 20 to 80 percent EtOAc / hexanes), to give 3.2 grams of Compound 207 as a pale yellow oil, m / z 298.0 (M + H) +. Compound 123 To a solution of Compound 122 (3.2 grams, 10.8 mmol) in tetrahydrofuran (100 milliliters), freshly prepared 1 M LiOH (10.8 mmol) was added thereto. The biphasic reaction was stirred vigorously at room temperature for 16 hours, before quenching with 1M HCl. The pH of the mixture was adjusted to 2.5-3, and then evaporated to a small volume. The mixture was partitioned between CH2Cl2 and brine (50 milliliters), and the aqueous layer was separated and extracted with CH2Cl2 twice. The combined CH2Cl2 layers were dried over anhydrous Na2SO4, and concentrated, to give 3.37 grams of Compound 123 as a pale yellow oil, which was used without further purification, m / z 316.0 (M + H) +, 338 (M + Na) +. Example CG Example CG was prepared following the same procedure as for Example C, only that Compound 123 was used in place of Compound 7. 1 H-NMR (CDCl 3, 500 MHz): 8.80 (s, 1H); 7.83 (s, 1H), 7.11-7.26 (m, 10H), 6.96 (s, 1H); 7.12-7.27 (m, 10H); 6.52 (br s, 1H), 6.40 (br s, 1H), 5.23 (s, 2H), 5.20 (m, 1H), 4.44 (dAB, 2H, J = 15.5 Hz), 4.39 (m, 1H), 4.11 (m, 1H), 3.80 (m, 1H), 3.61 (m, 2H), 3.28 (sep, 1H, J = 7.0 Hz); 2.94 (s, 3H), 2.79 (dd, 1H, J1 = 6.1 Hz, J2 = 13.4 Hz); 2.71 (m, 3H), 1.93 (m, 1H), 1.71 (m, 1H), 1.54 (m, 1H), 1.38 (d, 6H, J = 7.0 Hz) 1.37 (m, 1H). (:) +; m / z 707.3 (+ H) +), 729.2 (+ Na) +.
Preparation of Compound 100 Scheme 70 121 100 I. a. CDI, DIPEA, MeCN. Compound 100 was prepared using the same method as that used to prepare Compound 122, except that Compound 9 was replaced with Compound 68. Preparation of Example CH Scheme 71 I. EDCI / HOBt / Pr2NEt / THF; II. HCHO / NaBH (OAc) 3 / HOAc / CH3C; III. Compound 16 / Pr2NEt / CH3CN. Compounds 124 and 125 To a solution of Compound 29 (135 milligrams, 0.43 millimoles) and Compound 22 (116 milligrams, 0.43 millimoles) in tetrahydrofuran (5 milliliters), HOBt (70 milligrams, 0.52 millimoles), EDC (94 microliters, 0.52 millimoles), and di-isopropyl-ethyl-amine (150 microliters, 0.83 millimoles) were added. The mixture was stirred for 12 hours, and concentrated. Purification by reverse HPLC gave Compound 124 (70 milligrams) and Compound 125 (120 milligrams). Compound 124: 1 H NMR (CDCl 3) d 7.2-7.1 (10H, m), 7.0 (2H, s), 6.45 (2H, m), 6.15 (2H, m), 4.45 (4H, s), 4.1 (2H, m), 3.96 (2H, m), 3.3 (2H, m), 2.98 (6H, s), 2.7 (4H, m), 2.1 (2H, m), 1.6-1.3 (16H, m), 0.90 (12H , m). m / z 859.3 (M + H) +; Compound 125: m / z 564.3 (M + H) +. Compound 126 To a solution of Compound 125 (120 milligrams, 0.21 mmol) in CH3CN (1 milliliter), a solution of 37 percent formaldehyde (17 microliters, 0.23 mmol) was added, followed by HOAc (24 microliters, 0.42 mmol). ). The mixture was stirred for 2 hours, and NaBH (OAc) 3 (140 milligrams, 0. 63 millimoles). The mixture was stirred for a further 2 hours, and was diluted with EtOAc. The organic phase was washed with a saturated solution of Na 2 CO 3, water, and brine, and dried over Na 2 SO 4. The concentration gave Compound 126, which was used in the next step without further purification, m / z 578.3 (M + H) +. Example CH Example CH (26 milligrams) was prepared following the procedure used to prepare Example L, except that Compound 126 was used in place of Compound 22. HRN (CDCl 3) d 8.91 (1H, m), 7.82 (1H, m), 7.2-7.0 (11 H, m), 6.4 (1H, m), 6.2 (1H, m), 5.23-5.05 (2H, m), 4.44 (2H, s), 4.44 (1H, m), 4.2 (1 H, m), 3.95 (1 H, m), 3.32 (1 H, m), 2.98 (3 H, s), 2.8-2.5 (7 H, m), 2.15 (1 H, m), 1.7-1.2 (10H, m), 0.88 (6 H, m). m / z 719.3 (M + H) +. Preparation of Example Cl Scheme 72 I. HCHO / NaBH (OAc) 3 / HOAc / CH3CN; II. Compound 29 / EDCI / HOBt / iPr2NEt / THF.
Compound 127 Compound 127 (110 milligrams) was prepared following the procedure used to prepare Compound 126, except that Compound 8 was used in place of Compound 125. m / z 424.4 (M + H) +. Example Cl Example Cl (7 milligrams) was prepared following the procedure used to prepare Example C, except that Compounds 127 and 29 were used instead of Compounds 8 and 7. 1 H-NMR (CDCl 3) d 9.0 ( 1 H, s), 8.92 (1 H, s), 7.4-7.0 (11 H, m), 5.25 (2 H, m), 4.6-4.0 (5 H, m), 3.4 (1 H, m), 3.1-2.6 (10 H, m), 1.9 (1 H, m), 1.8 (10 H, m), 0.9 (6 H, m); m / z 719.2 (M + H) +. Preparation of Compound CJ Scheme 73 I. a. TFA / CH2Cl2; b. Na2C03; It. Compound 16 / iPr2NEt / CH3CN; III. Compound 29 / EDCI / HOBt / iPr2NEt / THF.
Compound 128 To a solution of Compound 21 (100 milligrams) in dichloromethane (5 milliliters), trifluoroacetic acid (1 milliliter) was added. The mixture was stirred for 3 hours, and the excess reagent was evaporated. The oil was diluted with EtOAc, and then diluted with a saturated solution of Na 2 CO 3 (twice), water (twice), and brine, and dried over Na 2 SO 4. The concentration gave Compound 128 (46 milligrams), m / z 267.1 (M + H) +. Compound 129 Compound 129 (44 milligrams) was prepared following the procedure for Compound 8, except that Compound 128 was used in place of Compound 22. m / z 408.10 (M + H) +. Example CJ Example CJ (55 milligrams) was prepared following the procedure of Example C, except that Compounds 129 and 29 were used instead of Compounds 8 and 7. 1 H-NMR (CDCl 3) d 8.81 (1 H, s) , 7.85 (1 H, s), 7.2-7.0 (11 H, m), 6.4 (1 H, m), 6.12 (1 H, m), 5.44 (2 H, m), 5.26 (2 H, s) , 4.85 (1 H, m), 4.70 (1 H, m), 4.4 (3 H, m), 4.06 (1 H, m), 3.25 (1 H, m), 2.98 (3 H, s), 2.78 (4 H, m), 2.21 (1 H, m), 1.38 (6 H, m), 0.88 (6 H, m); m / z 703.2 (M + H) +. Preparation of Compounds CK and CL Scheme 74 I. Compound 8 / EDC / HOBt; II. to. TFA; b. NaOH / THF. Example CK Example CK (88 milligrams) was prepared following the procedures used to prepare Example C, except that Compound 49 was used in place of Compound 7. m / z 749.2 (M + H) +. Example CL A mixture of Example CK (85 milligrams) and trifluoroacetic acid (5 milliliters) was stirred for 3 hours. Excess trifluoroacetic acid was evaporated, and the mixture was dried under a high vacuum. The mixture was dissolved in tetrahydrofuran (5 milliliters), and a 1.0N sodium hydroxide solution was added until the pH was 11. The solution was stirred for 10 minutes, and extracted with EtOAc. The organic phase was washed with water, brine, and dried over Na2SO4.
Concentration and purification by flash column chromatography (EtOAc) gave Example CL (66 milligrams). 1 H NMR (CDCl 3) d 8.81 (1 H, s), 7.84 (1 H, s), 7.30- 6. 96 (11 H, m), 5.22 (2 H, s), 4.90 (1 H, m), 4.45 (1 H, m), 4.35-4.0 (4 H, m), 3.8 (1 H, m), 3.6 (1 H, m), 3.21 (1 H, m), 2.95 (3 H, s), 2.8-2.6 (4 H, m), 2.0-1.4 (4 H, m), 1.25 (6H, m) . m / z 693.2 (M + H) +. Preparation of Example C Scheme 75 I. SOCI2 / MeOH; II. to. CDI / iPr2NEt; b. Compound 9; III. to. NaOH / THF / H20; b. HCI; IV. Compound 8 / EDC / HOBt. Compound 130 Compound 130 is commercially available from (TCI), and was used as received. Compound 131 To the solution of Compound 130 (510 milligrams, 3 mmol) in methanol (12 milliliters) at 0 ° C, thionyl chloride (0.5 milliliters, 6.6 mmol) was added dropwise. The mixture was stirred at 0 ° C for 30 minutes, and brought to reflux for 3 hours. The concentration gave Compound 131 as a white solid. Compound 132 To a stirred solution of Compound 131 (3 mmol) and di-isopropylamine (2 milliliters, 12 mmol) in dichloromethane (35 milliliters), CDI (486 milligrams, 3 mmol) was added. The mixture was stirred for 12 hours. Compound 9 was added, and the mixture was stirred for an additional 12 hours. Concentration and purification by flash column chromatography (CH2Cl2 / iPrOH = 1071) gave Compound 132 (414 milligrams), m / z 380.0 (M + H) +. Compound 133 Compound 133 was prepared following the procedure for Compound 67, except that Compound 132 was used in place of Compound 66. m / z 364.0 (M + H) +. Example CM Example CM (600 milligrams) was prepared following the procedure for Example C, except that Compound 133 was used in place of Compound 7. 1 H-NMR (CDCl 3) d 9.18 (1 H, s), 8.35 ( 1 H, s), 7.95 (1 H, s), 7.6 (1 H, m), 7.3-7.0 (11 H, m), 5.22 (2 H, m), 4.70 (1 H, m), 4.50 ( 2 H, m), 4.05 (1 H, m), 3.86 (3 H, s), 3.80 (2 H, m), 3.55 (1 H, m), 3.10 (1 H, m), 2.90 (3 H , s), 2.70 (4 H, m), 1.45 (10 H, m); m / z 757.3 (M + H) +. Preparation of Examples O, P, CN. and CO Scheme 76 I. Compound 16 / iPr2NEt; II. Compound 13d or Compound 49 / EDC / HOBt; III. to. TFA; b. NaOH / THF. Example O Example O (17 milligrams) was prepared following the procedure for Example C, except that Compounds 46 and 49 were used instead of Compounds 8 and 7. m / z 749.3 (M + H) +. Example CN The CN Example (22 milligrams) was prepared following the procedure used to prepare Example C, except that Compounds 46 and 13e were used instead of Compounds 8 and 7. m / z 763.2 (M + H) +.
Example P Example P (12 milligrams) was prepared following the procedures used to prepare Example CM, except that Example O was used instead of Example CL. 1 H-NMR (CDCl 3) d 8.76 (1 H, s), 7.79 (1 H, s), 7.25-6.9 (11 H, m), 6.51 (1 H, broad), 5.42 (1 H, m), 5.18 (2 H, m), 4.42 (2 H, m), 4.22 (1 H, m), 4.10 (1 H, m), 3.95 (1 H, m), 3.79 (1 H, m), 3.58 (1 H , m), 3.23 (1 H, m), 2.93 (3 H, s), 2.9-2.5 (4 H, m), 1.6-1.2 (10 H, m); m / z 693.2 (M + H) +. Compound CQ Compound CO (13 milligrams) was prepared following the procedure used to prepare Example CL, except that Example CN was used in place of Compound CK.1H RN (CDCI3) d 8.85 (1H, m), 7.88 (1 H, m), 7.3-7.0 (11 H, m), 6.55 (1 H, m), 6.24 (1 H, m), 5.45 (1 H, m), 5.23 (2 H, m), 4.6 (2 H, m), 4.2 (1 H, m), 4.0 (2 H, m), 3.7 (1 H, m), 3.5 (1 H, m), 3.02 (3 H, s), 2.70 (4 H, m), 1.6- I.0 (13 H, m); m / z 707.3 (M + H) +. Preparation of Examples CP-CS Scheme 77 II CR R »H CS B 55 Me I. Compound 16 / Pr2NEt; II. Compound 13d or 49 / EDC / HOBt; III. to. TFA; b. NaOH / THF. Compound 34 Compound 134 was prepared using the procedure described for Compound 76, except that CBZ-D-alaninol was used in place of CBZ-L-alaninol. Compound 135 Compound 135 was prepared using the procedure used to prepare Compound 8, except that Compound 134 was used in place of Compound 22. CP Example CP Example (12 milligrams) was prepared following the procedure used to prepare Example C , except that Compounds 135 and 49 were used instead of Compounds 8 and 7. m / z 597.2 (M + H) +. Example CQ Example CQ (11 milligrams) was prepared following the procedure used to prepare Example C, except that Compounds 135 and 13d were used instead of Compounds 8 and 7. m / z 611.2 (M + H) +.K.
Example CR Example CR (7 milligrams) was prepared following the procedure used to prepare Example P, except that Example CP was used instead of Example O. 1 H NMR (CDCl 3) d 8.82 (1 H, s), 7.88 ( 1 H, s), 7.02 (1 H, s), 6.92 (1 H, m), 5.28 (2 H, s), 5.10 (1 H, m), 4.5 (2 H, m), 4.15 (2 H , m) 3.88 (1 H, m), 3.8-3.5 (2 H, m), 3.35 (1 H, m), 3.0 (3 H, s), 1.5-1.0 (16 H, m); m / z 541.1 (M + H) +. Example CS Example CS (8 milligrams) was prepared following the procedure used to prepare Example CO, except that Example CQ was used instead of the CN Example. 1 H NMR (CDCl 3) d 8.83 (1 H, s), 7.88 (1 H, s), 6.98 (1 H, s), 6.81 (1 H, m), 6.58 (1 H, m), 5.28 (2 H) , s), 5.18 (1 H, m), 4.4-4.3 (2 H, m), 4.03 (1 H, m), 3.85 (1 H, m), 3.58 (2 H, m), 3.3 (1 H , m), 2.99 (3 H, s), 1.5-0.98 (19 H, m); m / z 555.2 (M + H) +. Preparation of the Examples CT-CV Scheme 78 I. PhCHO / NaBH4; II. Compound 16 / iPr2NEt; III. Compound 13d / EDC / HOBt. Compound 136 Compounds 136a-c are commercially available (Sigma-Aldrich). Compound 137 To a solution of Compound 136 (20 mmol) in methanol (25 milliliters) benzaldehyde (40 mmol) was added dropwise. The mixture was stirred for 2 hours, and cooled to 0 ° C. Sodium borohydride (44 mmol) was added in portions. The mixture was heated to 25 ° C, and stirred for 2 hours. Acetic acid (10 milliliters) was added, and the mixture was stirred for 10 minutes. The methanol was removed, and the mixture was partitioned between EtOAc and a 3N NaOH solution. The organic layer was separated, and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with water, brine, and dried over Na2SO4. The concentration gave Compound 137. Compound 138 Compound 138 was prepared following the procedure used to prepare Compound 8, except that Compound 137 was used in place of Compound 22. Example CT Example CT (70 milligrams) was prepared following the procedure used to prepare Example C, except that Compounds 29 and 138a were used instead of Compounds 13a and 8. 1 H-NMR (CDCl 3) d 8.79 (1 H, s), 7.86 (1 H, s), 6.97 (1 H7 s), 6.49 (1 H, m), 6.15 (1 H, m), 5.28 (2 H, s), 5.20 (1 H7 m), 4.44 (2 H, m), 4.05 (1 H, m), 3.25 (5 H, m), 3.0 (3 H, s), 2.24 (1 H, m), 1.8-1.45 (4 H, m), 1.38 (6 H, m), 0.97 (6 H, m); m / z: 525.2 (M + H) +. Example CU Example CU 8140 milligrams) was prepared following the procedure used to prepare Example C, except that Compounds 29 and 138b were used in place of Compounds 13a and 8. 1 H-NMR (CDCl 3) d 8.78 (1 H , s), 7.85 (1 H, m), 7.4-7.05 (10 H, m), 6.93 (1 H, s), 5.90 (1 H, m), 5.35 (2 H, s), 4.9-4.6 ( 2 H, m), 4.6-4.4 (4 H, m), 4.2 (1 H, m), 3.4-3.05 (5 H, m), 3.0 (3 H, s), 2.0 (1 H, m), 1.8-1.3 (10 H, m), 0.90 (6 H, m); m / z: 705.2 (M + H) \ Example CV Example CV (145 milligrams) was prepared following the procedure used to prepare Example C, except that Compounds 29 and 138c were used instead of Compounds 13a and 8. 1 H-NMR (CDCl 3) d 8.76 (1 H, m), 7.86 (1 H, m), 7.4-7.02 (10 H, m), 6.97 (1 H, m), 5.75 (1 H, m), 5.38 (2 H, m), 4.95-4.3 (6 H, m), 4.15 (1 H, m), 3.4-3.0 (5 H, m), 3.0 (3 H, s), 2.2-1.6 (3 H, m), 1.4 (6 H, m), 0.88 (6 H7 m); m / z: 691.2 (M + H) +. Preparation of Example CW CW Example CW could be prepared, for example, by reacting Compound 8 with a compound having the following structure: where "LG" is a leaving group, such as a halogen. These compounds could be prepared by the degradation of a carbon atom of the corresponding carboxylic acid or ester (eg, Compounds 28 or 29) by known methods, such as the Hunsdieker reaction or the Kochi reaction, or similar methods. IC50 determinations for human liver cytochrome P450. Materials and General Methods The reserved human hepatic microsomal fraction (n >; 15 donors) was obtained in BD-Gentest (Woburn, MA), which also supplied hydroxy-terfenadine, 4'-hydroxy-diclofenac, and the NADPH regenerating system. Ritonavir was prepared from a commercial oral solution Norvir® (Abbott Laboratories, Abbott Park, IL). Other reagents were from Sigma Aldrich (St. Louis, MO), and included terfenadine, fexofenadine, BRL 15572, diclofenac, and mefenamic acid. Incubations were carried out in duplicate in 50 mM potassium phosphate buffer, pH 7.4, using the system NADPH regenerator, as described by the manufacturer. The final microsomal protein concentrations had previously been determined within the linear range for the activity, and resulted in a consumption of less than 20 percent of the substrate during the course of the incubation. The final substrate concentrations used were equal to the apparent Km values for the activities determined under the same conditions. The inhibitors were dissolved in dimethyl sulfoxide, and the final concentration of dimethyl sulfoxide, both from the substrate and from the inhibitor vehicles, was 1 percent (volume / volume). The incubations were carried out at 37 ° C with agitation, and were initiated by the addition of the substrate. Aliquots were then removed at 0, 7, and 1 5 minutes. The samples were quenched by treatment with a mixture of acetonitrile, formic acid, and water (94.8 percent / 0.2 percent / 5 percent, volume / volume / volume) containing the internal standard. The precipitated protein was removed by centrifugation at 3,000 revolutions per minute for 10 minutes, and then the extracts of the supernatant were subjected to LC-MS analysis. The LC-MS system consisted of a U PLC Waters Acquity, with a binary solvent handler, a refrigerated sample organizer (8 ° C), and a sample handler, interconnected with a Micromass Quattro Premier row mass spectrometer operating in the electrospray ionization mode. The col umna was a Waters Acquity U PLC BEH C 1 8, 2.1 x 50 millimeters, with a pore size of 1.7 microns. The mobile phases consisted of mixtures of acetonitrile, formic acid and water, the composition for mobile phase A being 1 percent / 0.2 percent / 98.8 percent (volume / volume / volume), and the former being for mobile phase B of 94.8 percent / 0.2 percent / 5 percent volume / volume / volume). The injection volumes were 5 microliters, and the flow rate was 0.8 milliliters / minute. The concentrations of the metabolites were determined by reference to the standard curves generated with authentic analytes under the same conditions as the incubations. The IC50 values (the inhibitor concentration that reduces CYP3A activity by 50 percent) were calculated by non-linear regression, using the GraphPad Prism 4.0 software, and a sigmoidal model. CYP3A Inhibition Assay The potencies of the compounds were evaluated as inhibitors of the human liver P450 cytochromes of the CYP3A subfamily (particularly CYP3A4) using terfenadine oxidase, a well characterized selective CYP3A activity described in Ling, K-H. J. et al., Druq Metab. Pispos. 23, 631-636 (1995), and Jurima-Romet et al., Druq Metab. Pispos. 22, 849-857 (1994). The final concentrations of the microsomal protein and the terfenadine substrate were 0.25 milligrams / milliliter and 3 μ ?, respectively. Metabolic reactions were terminated by treatment with 7 volumes of the shutdown solution containing BRL 15572 0.1 μ as internal standard. An additional 8 volumes of water were added to the centrifugation, and aliquots of the supernatant were removed for analysis. For the LC-S analysis, the chromatographic elution was achieved by a series of linear gradients, starting at 20 percent of B and holding for 0.5 minutes, then increasing to 80 percent for 1.5 minutes, holding for 0.4 minutes, and then returning to the initial conditions for 0.05 minutes. The system was allowed to rebalance for at least 0.25 minutes before the next injection. The mass spectrometer was operated in the positive ion mode, and the following pairs of precursor ([M + H] +) / ion of the product were monitored and quantified using the MassLynx 4.0 software (SPA4, 525): Terfenadine 488.7 / 452.4, Fexofenadine 502.7 &466.4, and BRL 15572 407.5 / 209.1. The activity of terfenadine oxidase was determined from the sum of the metabolites of hydroxy-terfenadine and carboxy-terfenadine (fexofenadine). Inhibition assay of CYP2C9 The potencies of the compounds were evaluated as inhibitors of human hepatic CYP2C9, using diclofenac 4'-hydroxylase, a specific activity for this enzyme, as described in Leeman, T., et al., Life Sci. 52 , 29-34 (1992). The final concentrations of the microsomal protein and diclofenac substrate were 0.08 milligrams / milliliter and 4 μ, respectively. Metabolic reactions were terminated by treatment with three volumes of quenching solution containing 1 μm mefenamic acid. as an internal standard. After centrifugation, 4 additional volumes of water were added. Then the aliquots of the supernatant were subjected to LC-S analysis. For the LC-MS analysis, the chromatographic elution was achieved by a series of linear gradients starting at 20 percent B and holding for 0.3 minutes, then increasing to 99 percent of B for 1.2 minutes, holding for 0.5 minutes, and then returning to the initial conditions for 0.25 minutes. The system was allowed to rebalance for at least 0.25 minutes before the next injection. The mass spectrometer was operated in the negative ion mode, and the following pairs of precursor (([MH] ') / ion of the product were monitored and quantified: 4'-hydroxy-diclofenac 312.4 / 294.2 and mefenamic acid 242.4 / 224.2 Biological Assays Used for the Characterization of HIV Protease Inhibitors HIV-1 Protease Enzyme Assay (Ki) The assay is based on the fluorimetric detection of the dissociation of the synthetic hexapeptide substrate by the HIV-protease. in a defined reaction regulator, as was initially described by MV Toth and GR Marshall, Int. T. Peptide Protein Res. 36, 544 (1990) (incorporated herein by reference) reference in its entirety for all purposes). The assay employed (2-amino-benzoyl) Thr-lle-Nle- (p-nitro) Phe-Gln-Arg as the substrate, and the recombinant HIV-1 protease expressed in E. coli as the enzyme. Both reagents were supplied by Bachem California, Inc. (Torrance, CA, Catalog Number H-2992). The regulator for this reaction was 100 mM ammonium acetate, pH 5.3, 1M sodium chloride, 1 mM ethylene diamine tetraacetic acid, 1 mM dithioerythritol, and 10 percent dimethyl sulfoxide. To determine the inhibition constant Ki, a series of solutions was prepared containing an identical amount of the enzyme (from 1 to 2.5 nM), and the inhibitor to be tested in different concentrations in the reaction regulator. The solutions were subsequently transferred to a 96-well white plate (190 microliters each), and pre-incubated for 15 minutes at 37 ° C. The substrate was solubilized in 100 percent dimethyl sulfoxide, at a concentration of 800 μ ?, and 10 microliters of the substrate 800 μ? to each well to reach a final substrate concentration of 40 μ ?. Real-time reaction kinetics were measured at 37 ° C, using a Gemini 96-well plate fluorimeter (Molecular Devices, Sunnyvale, CA) at a? (??) = 330 nanometers, and A (Em) = 420 nanometers . The initial rates of the reactions with different concentrations of inhibitor were determined, and the Ki value (in units of picomolar concentration) was calculated, using the EnzFitter program (Biosoft, Cambridge, United Kingdom) according to an algorithm for tight binding competitive inhibition described by Ermolieff J., Lin X., and Tang J., Biochemistry 36, 12364 (1997). HIV-1 Protease Enzyme Assay (IC ^ n) As for the previous K1 assay, the IC50 assay relies on the fluorimetric detection of the cleavage of the synthetic hexapeptide substrate by the HIV-1 protease in a regulator of defined reaction, as was initially described by MV Toth and GR. Marshall, Int. T. Peptide Protein Res.36, 544 (1990). The assay employed (2-amino-benzoyl) Thr-lle-Nle- (p-nitro) Phe-Gln-Arg as the substrate, and the recombinant HIV-1 protease expressed in E. coli as the enzyme. Both reagents were supplied by California, Inc. (Torrance, CA; Catalog Numbers H-2992 and H-9040, respectively). The regulator for this reaction was 100 mM ammonium acetate, pH 5.5, 1 M sodium chloride, 1 mM ethylene diamine tetraacetic acid., and 1 mM dithioerythritol, and 10 percent dimethyl sulfoxide. To determine the IC 50 value, 170 microliters of the reaction regulator was transferred to the wells of a 96-well white microtiter plate. A series of triple dilutions in dimethyl sulfoxide of the inhibitor to be tested was prepared, and 10 microliters of the resulting dilutions were transferred to the wells of the microtiter plates. Ten microliters of a 20-50 nM enzymatic delivery solution in reaction regulator was added to each well of the 96-well plate, to provide a final enzyme concentration from 1 to 2.5 nM. The plates were then pre-incubated for 10 minutes at 37 ° C. The substrate was solubilized in 100 percent dimethyl sulfoxide at a concentration of 400 μ ?, and 10 microliters of the 400 μ substrate was added. to each well to reach a final substrate concentration of 20 μ ?. Real-time reaction kinetics were measured using a Gemini 96-well plate fluorimeter (Molecular Devices, Sunnyvale, CA) at a? (??) = 330 nanometers, and one? (Em) = 420 nanometers. The initial rates of the reactions with different concentrations of inhibitor were determined, and the IC50 value (in units of nanomolar concentration) was calculated using the GraphPad Prism R software, to adjust the non-linear regression curves. Cell Culture Assay Anti-HIV-1 (EC ^ n) The assay is based on the quantification of the cytopathic effect associated with HIV-1, by means of a colorimetric detection of the viability of the cells infected by virus in the presence or absence of the inhibitors tested. The cell death induced by HIV-1 was determined using a metabolic substrate of 2,3-bis- (2-methoxy-4-nitro-5-sulfophenyl) -2H-tetrazolium-5-carboxanilide (XTT), which is converted only by intact cells in a product with specific absorption characteristics, as described by Weislow OS,. Kiser R, Fine DL, Bader J, Shoemaker RH and Boyd M. R., J. Nati. Cancer Inst. 81, 577 (1989) (incorporated herein by reference in its entirety for all purposes).
MT2 cells (NIH AIDS reagent program, Catalog Number 237), maintained in RPMI-1640 medium supplemented with 5 percent fetal bovine serum and antibiotics, were infected with the wild type HIV-1 strain IIIB (Advanced Biotechnologies , Columbia, MD) for 3 hours at 37 ° C, using the virus inoculum corresponding to a multiplicity of infection equal to 0.01. The infected cells in the culture medium were distributed in a 96-well plate (20,000 cells in 100 microliters / well), and incubated in the presence of a set of solutions containing five-fold serial dilutions of the tested inhibitor (100 microliters / well) for 5 days at 37 ° C. Samples with untreated, infected, and untreated infected control cells were also distributed in the 96-well plate and incubated under the same conditions. To determine the antiviral activity of the tested inhibitors, an XTT solution of substrate (6 milliliters per assay plate), at a concentration of 2 milligrams / milliliter in phosphate buffered serum, pH 7.4, was heated in a water bath during 5 minutes at 55 ° C, before adding 50 microliters of N-methyl-phenazonium metasulfate (5 micrograms / milliliter) per 6 milliliters of XTT solution. After removing 100 microliters of medium from each well of the assay plate, 100 microliters of the XTT substrate solution was added to each well. The cells and the XTT solution were incubated at 37 ° C for 45 to 60 minutes in a C02 incubator. To inactivate the virus, 20 were added microliters of Triton X-1 00 at 2 percent to each well. The viability, determined by the amount of metabolites of XTT produced, was quantified spectrophotometrically, by the absorbance at 450 nanometers (with subtraction of the absorbance of the bottom at 650 nanometers). The test data were expressed as the percentage of absorbance relative to the untreated control, and the 50 percent effective concentration (EC50) was calculated as the concentration of the compound that made an increase in the production percentage of the XTT metabolite in infected cells treated with the compound up to 50 percent of the produced by uninfected cells without compound. Anti-VI Cell Culture Assay H- (EC ^) in the Presence of Human Serum or 40% Human Serum Proteins This assay is almost identical to the anti-VI H-1 cell culture assay described above, except that infection was done in the presence or absence of 40 percent human serum (Type AB Male Cambrex 1 4-498E) or human serum proteins (a-human acid glycoprotein, Sigma G-9885; human serum albumin or, Sigma A1 653, from 96 to 99 percent) in the physiological concentration. Cell death induced by VI H-1 was determined as described above, except that the infected cells distributed in the 96-well plate were incubated in 80 percent human serum (double concentration) or 2 milligrams / milliliter of glycoprotein. of a-human acid plus 60 milligrams / milli liters of HSA (double concentration), instead of in the culture medium.
Cytotoxicity Cell Culture Assay (ECsn) The assay is based on the evaluation of the cytotoxic effect of the compounds tested using a metabolic substrate of 2,3-bis- (2-methoxy-4-nitro-5-sulfophenyl) -2H- tetrazolium-5-carboxanilide (XTT), as described by Weislow OS, Kiser R, Fine D. L, Bader J, Shoemaker RH and Boyd MR, J. Nati. Cancer Inst. 81, 577 (1989). This assay is almost identical to the previous assay described (HIV-1 cell culture assay), except that the cells did not. They were infected. Cell death (or growth reduction) induced by the compound was determined, as described above. MT-2 cells maintained in RPMI-1640 medium supplemented with 5 percent fetal bovine serum and antibiotics, were distributed in a 96-well plate (20,000 cells in 100 microliters / well), and incubated in the presence or in absence of quintuple serial dilutions of the tested inhibitor (100 microliters / well) for 5 days at 37 ° C. Controls included untreated infected cells, and infected cells protected by 1 μ? of P4405 (Podofilotoxin, Sigma, Catalog Number P4405). To determine cytotoxicity, a solution of XTT (6 milliliters per test plate), at a concentration of 2 milligrams / milliliter, in phosphate buffered serum, pH 7.4, was heated in the dark in a water bath for 5 minutes at 55 ° C, before adding 50 microliters of N-methyl phenazonium metasulfate (5 micrograms / milliliter) per 6 milliliters of solution XTT After removing 1000 microliters of the medium from each well of the assay plate, 1000 microliters of the XTT substrate solution was added to each well. The cells and the XTT solution were incubated at 37 ° C for 45 to 60 minutes in an incubator with C02. To inactivate the vius, 20 microliters of Triton X-1 00 was added to 2 percent in each well. The viability, determined by the amount of XTT metabolites produced, is quantified spectrophotometrically, by the absorbance at 450 nanometers (with subtraction of the absorbance of the bottom at 650 nanometers). The test data is expressed as the percentage of absorbance relative to the untreated control, and the 50-fold cytotoxicity concentration (EC50) was calculated as the concentration of the compound that caused an increase in the percentage of cell growth in the cells treated with the compound up to 50 percent of the cell growth provided by the uninfected cells, without com position. Experimental data based on the representative Examples A-CV, demonstrate that the compounds of the Formula (I) of the present invention can have a CYP450 3A4 inhibitory activity in a range represented by an IC50 of about 1 00 nM a approximately 4,700 nM, and an inhibitory activity of CYP450 2C9 in a range represented by an IC 50 of about 1 00 nM to about 4,200 nM.
The experimental data based on the representative Examples A-CV, demonstrate that the compounds of the Formula (I) of The present invention may have a protease inhibitory activity in a range represented by an HIV EC50 of about 140 nM to more than about 1,000 nM. The experimental data based on the representative Examples P, S, and T, have an inhibitory activity of CYP450 3A4 in a range represented by an IC50 of about 80 to 150 nM, an inhibitory activity of CYP450 2C9 in a range represented by an IC50 of about 1,000 to 10,000 nM, and a protease inhibitory activity in a range represented by an HIV EC5o greater than about 20,000 nM.

Claims (1)

  1. CLAIMS 1. A compound of Formula I: or a pharmaceutically acceptable salt, solvate, and / or ester thereof, wherein: L is selected from the group consisting of -C (R6) 2-, -C (O) -, -S (02) -, -N (R7) -C (0) -, and -OC (O) -; L2 is a covalent bond, -C (R6) 2- or -C (O) -; each L3 is independently a covalent bond, an alkylene, or substituted alkylene; each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, -O-, -CH2-O-, and -NH-; each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl, with the proviso that, when A is H, p is 0; Z1 and Z2 are each independently -O- or -N (R7) -; Y and X are independently selected from the group consisting of heterocyclyl and heterocyclyl-alkyl; each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R1, R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl-alkyl, and substituted aryl-alkyl; each R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxy-alkyl, hydroxy-alkyl, aryl-heteroalkyl, substituted aryl-heteroalkyl, aryl-alkyl, substituted aryl-alkyl, heterocyclyl-alkyl, heterocyclyl -substituted alkyl, amino-alkyl, substituted amino-alkyl, -alkylene-C (O) -OH, -alkylene-C (0) -0-alkyl, -alkylene-C (0) -amino, -alkylene-C ( 0) -alkyl; R4 and R6 are independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, -CN; m is 1 or 2; n is 0 or 1; Y each p is independently O or 1. 2. The compound of claim 1, wherein n is 1. 3. The compound of claim 2, wherein L2 is -CH (R6) -. 4. The compound of claim 2, wherein Y is heterocyclyl-alkyl. 5. The compound of claim 2, wherein X is heterocyclyl-alkyl. 6. The compound of claim 2, wherein Z is -N (R7) -. 7. The compound of claim 2, wherein each A is independently substituted aryl or ari. 8. The compound of claim 1, wherein: L1 is -C (O) -; each A is independently aryl or substituted aryl; R1 is H or alkyl; each R2 is independently H, alkyl, substituted alkyl, or heteroalkyl; R3, R4, R5, and R6 are each H; each R7 is independently H, alkyl, or carbocyclyl; R8 is H or alkyl; R9 is H; X-R9 is: 7. #} that-; and p is 0. 9. The compound of claim 8, which has a formula: 10. A compound of the Formula IID: Formula IID or a pharmaceutically acceptable salt, solvate, and / or ester thereof, wherein: L1 is selected from the group consisting of -C (R6) 2-, -C (O) -, -S (02) -, -N (R7) -C (0) -, and -OC (O) -; each L3 is independently a covalent bond, an alkylene, or substituted alkylene; each L4 is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, -O-, -CH2-0-, and -NH-; each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl, with the proviso that, when A is H, p is 0; Z1 and Z2 are each independently -O- or -N (R7) -; Y and X are independently selected from the group consisting of heterocyclyl and heterocyclyl-alkyl; each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R \ R3, and R5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl-alkyl, and substituted aryl-alkyl; R2 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxy-alkyl, hydroxy-alkyl, aryl-heteroalkyl, substituted aryl-heteroalkyl, aryl-alkyl, substituted aryl-alkyl, heterocyclyl-alkyl, heterocyclyl- substituted alkyl, amino-alkyl, amino-substituted alkyl, -alkylene-C (O) -OH, -alkylene-C (0) -0-alkyl, -alkylene-C (0) -amino, -alkylene-C (0) -alkyl; R4 and R6 are independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, -CN; and each p is independently 0 or 1. 11. The compound of claim 10, wherein: L1 is -C (R6) 2-; each L3 is alkylene; each A is aryl or substituted aryl; X and Y are heterocyclyl-alkyl; Z1 is -N (R7) -; and Z2 is -O-. 12. A compound selected from the group consisting of: 410 411 ?? 414 ?? 25 417 pharmaceutically acceptable salts, solvates, esters, and / or stereoisomers thereof. 13. A compound of the Formula NA: Formula II A or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or ester thereof, wherein: R 11 and R 16 are each independently heterocyclyl, or substituted heterocyclyl; and R12, R13, R14, and R15 are each independently H, -alkyl of 1 to 4 carbon atoms, -alkyl of 1 to 4 carbon atoms substituted, aryl-alkyl, or aryl-substituted alkyl. The compound of claim 13, wherein: R 13 is H, -alkyl of 1 to 4 carbon atoms, - (CH 2) 0. - (CH2) 0.3CR 7R18NR 7C (O) - NR20R21, - (CH2) 1.3C (0) R22; - (CH2) 1.3S (0) 2R22, O - (CH ^ .aR23; R14 and R15 are each independently H, -alkyl 1 to 4 carbon atoms, or ril-alkyl; R 7 and R 18 are each independently H or alkyl of 1 to 3 carbon atoms; R19 is H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R20 and R21 are each independently H, -alkyl of 1 to 3 carbon atoms, -C (0) R17, or -S (0) 2R17; or R20 and R21, taken together with the carbon atom to which they are attached, form an unsubstituted or substituted heterocyclyl ring of 5-6 membered, containing 1 to 2 heteroatoms selected from the group consisting of N and O; R22 is H, -alkyl of 1 to 3 carbon atoms, -OR19, or -NR20R21; and R23 is an unsubstituted or substituted heterocyclyl ring of 5 to 6 members, containing 1 to 2 heteroatoms selected from the group consisting of N and O. The compound of claim 14, wherein the heterocyclyl ring from 5 to 6 unsubstituted or substituted members formed by R20 and R21, and the unsubstituted or substituted 5- to 6-membered heterocyclyl ring of R23, are each independently unsubstituted or substituted with an alkyl of 1 to 2 carbon atoms. 16. The compound of claim 14, wherein: R13 is - (CH2) 0.iCR 7R18OR19. 17. The compound of claim 14, wherein: R13 is - (CH2) 0.3CR17R 8NR20R21, or - (CH2) 0.3CR17R 8NR17C (O) -NR20R21. 18. The compound of claim 14, wherein: R1 R12, R13, R4, R15, and R16 are each independently selected from the following Table: Formula IIB or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or ester thereof, wherein: Rioa and Riob are each independently H or -alkyl of 1 to 4 carbon atoms; R12 is H or -CH2; R 13 is H, -alkyl of 1 to 4 carbon atoms, - (CH 2) 0. ! CR ^ R ^ OR19; - (CH2) o.3CR17R18NR20R21, - (CH2) 0.3CR17R18NR17C (O) -NR 0R2 ', - (CH2) 1.3C (0) R22; - (CH2) 1.3S (0) 2R22, OR - (CH2) 1.3R23; R 14 and R 5 are each independently H, -alkyl of 1 to 4 carbon atoms, aryl-alkyl, or aryl-substituted alkyl; R17 and R18 are each independently H or alkyl of 1 to 3 carbon atoms; R19 is H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R20 and R21 are each independently H, -alkyl of 1 to 3 carbon atoms, -C (0) R17, or -S (0) 2R17; or R20 and R21, taken together with the carbon atom to which they are attached, form an unsubstituted or substituted 5- to 6-membered heterocyclyl ring, containing 1 to 2 heteroatoms selected from the group consisting of N and R22 is H, -alkyl of 1 to 3 carbon atoms, -OR19, or -NR20R21; and R23 is an unsubstituted or substituted heterocyclyl ring of 5 to 6 members, containing 1 to 2 heteroatoms selected from the group consisting of N and O. The compound of claim 19, wherein the heterocyclyl ring from 5 to 6 unsubstituted or substituted members formed by R20 and R21, and the unsubstituted or substituted 5- to 6-membered heterocyclyl ring of R23, are each independently unsubstituted or substituted with an alkyl of 1 to 2 carbon atoms. 21. A compound of the Formula MC: Formula MC or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or ester thereof, wherein: R13 is H, -alkyl of 1 to 4 carbon atoms, - (CH2) o- Ri7Ri8ORi9 > (CH2) 0.3CR17R18NR20R21, - (CH2) 0.3CR17R18N R17C (0) NR20R2, - (CH2) ^. 3C (0) R 2, or - (CH2), 3fí23; R17 and R18 are each independently H or alkyl of 1 to 3 carbon atoms; R19 is H, -alkyl of 1 to 4 carbon atoms, or aryl-alkyl; R20 and R21 are each independently H, -alkyl of 1 to 3 carbon atoms, -C (0) R17, or -S (0) 2R17; or R20 and R21, taken together with the nitrogen atom to which they are attached, form a 5-6 membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O; R22 is H, -alkyl of 1 to 3 carbon atoms, -OR19, or -NR20R21; and R23 is a 5-6 membered heterocyclyl ring containing from 1 to 2 heteroatoms selected from the group consisting of N and O. 22. The compound of claim 21, wherein the heterocyclyl ring is from 5 to 6. unsubstituted or substituted members formed by R20 and R21, and the unsubstituted or substituted 5- to 6-membered heterocyclyl ring of R23, are each independently unsubstituted or substituted with an alkyl of 1 to 2 carbon atoms. 23. The compound of claim 21, wherein: R13 is - (CH2) 0.3CR 7R18NR20R21, or - (CH2) 0.3CR 7R18NR17C (O) -NR20R21. 24. The compound of claim 21, wherein: R13 is -CH2OH, -CH2CH2NHC (0) CH3, or A compound that is or a pharmaceutically acceptable salt and / or a solvate thereof. 27. A compound that is: or a pharmaceutically acceptable salt, solvate, stereoisomer and / or ester thereof. 2 or a pharmaceutically acceptable salt, solvate, and / or ester thereof. 29. A compound that is: or a sa will mechanically accept e, stereoisomer, and / or solvate thereof. 30. A compound that is: or a pharmaceutically acceptable salt and / or solvate thereof. 31 A method for improving the pharmacokinetics of a drug, which is metabolized by cytochrome P450 mono-oxygenase, which comprises administering to a patient treated with this drug, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. 32. The method of claim 31, wherein said administration comprises administering a therapeutically effective amount of a combination comprising said drug and the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or ester of the compound of the Formula I 33. A method for improving the pharmacokinetics of a drug, which is metabolized by cytochrome P450 mono-oxygenase, which comprises administering to a patient treated with this drug, a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and / or ester thereof. 34. The method of claim 33, wherein the drug metabolized by cytochrome P450 is a p Rotease inhibitor compound of VI H, a non-nucleoside reverse transcriptase inhibitor of VI H, a nucleoside reverse transcriptase inhibitor. , an inhibitor of reverse transcriptase of VI H that is nucleotide, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, capsid polymerization inhibitors, other drugs for the treatment of HIV, an interferon, a ribavirin analog , an NS3 protease inhibitor, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a non-nucleoside inhibitor of HCV, NS5a inhibitors, NS5b polymerase inhibitors, other drugs for the treatment of HCV, or mixtures thereof. 35. The method of claim 34, wherein the drug is: 6- (3-chloro-2-fluoro-benzyl) -1 - ((2S) -1-hydroxy-3-methyl-butan-2-yl acid ) -7-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. 36. The method of claim 34, wherein the drug is atazanavir. 37. The method of claim 35, wherein the compound is: The method of claim 36, wherein the compound 39. The method of claim 33, wherein the drug and the compound or salt of claim 13 are administered as a single composition to the patient. 40. A method for increasing levels in the blood plasma of a drug, which is metabolized by cytochrome P450 mono-oxygenase, which comprises administering to a patient treated with this drug, a therapeutically effective amount of a compound of the claim 1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. 41 The method of claim 40, wherein said administration comprises administering a therapeutically effective amount of a combination comprising said drug and the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or ester of the compound of the formula I. 42. The method of claim 40, wherein the amount of the compound of Formula I administered is effective to inhibit cytochrome P450 mono-oxygenase. 43. A method for inhibiting cytochrome P450 mono-oxygenase in a patient, which comprises administering to a patient in need thereof, an amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof , effective to inhibit cytochrome P450 mono-oxygenase. 44. A method for inhibiting cytochrome P450 mono-oxygenase in a patient, which comprises administering to a patient in need thereof, an amount of a compound of claim 13, or a pharmaceutically acceptable salt, solvate, and / or ester. of it, effective to inhibit cytochrome P450 mono-oxygenase. 45. A method for the treatment of an HIV infection, which comprises administering to a patient in need, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. , in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, non-nucleoside HIV reverse transcriptase inhibitors, HIV reverse transcriptase inhibitors that are nucleosides, HIV transcriptase inhibitors that are nucleotides, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, G6PD inhibitors and NADH oxidase, CCR5 inhibitors, other drugs for the treatment of HIV, and mixtures thereof. 46. A method for the treatment of an HIV infection, which comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of claim 13, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, in combination with a therapeutically effective amount of one or more agents Additional therapeutics selected from the group consisting of HIV protease inhibitor compounds, non-nucleoside reverse transcriptase inhibitors of HIV, HIV reverse transcriptase inhibitors which are nucleosides, HIV transcriptase inhibitors which are nucleotides, inhibitors of HIV integrase, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, G6PD inhibitors and NADH oxidase, CCR5 inhibitors, other drugs for the treatment of HIV, and mixtures thereof. 47. The method of claim 46, wherein: (1) the mentioned HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir , darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, NI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100 , DG35, and AG 1859; (2) non-nucleoside HIV reverse transcriptase inhibitors are selected from the group consisting of capravirin, emivirine, delaviridin, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806; (3) Inhibitors of HIV reverse transcriptase which are nucleotides are selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (± - FTC), D-d4FC, emtricitabine, phosphazide, fozivudine-tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine-tidoxil (formerly HDP 99,0003); and (4) the HIV reverse transcriptase inhibitors that are nucleotides are selected from the group consisting of tenofovir and adefovir; (5) HIV integrase inhibitors are selected from the group consisting of curcumin, curcumin derivatives, chicoric acid, quicoric acid derivatives, 3,5-dicaffeoyl-quinic acid, 3,5-dicarboxylic acid derivatives, quininic, aurintricarboxylic acid, aurintricarboxylic derivatives, phenethyl-ester of caffeic acid, phenethyl ester derivatives of caffeic acid, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, S-1360, zintevir (AR-177), L- 870812, and L-870810, MK-0518 (raltegravir), BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA 011; (6) gp41 inhibitors are selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144; (7) the CXCR4 inhibitor is AMD-070; (8) the input inhibitor is SP01 A; (9) the gp120 inhibitor is BMS-488043 or BlockAide / CR; (10) the inhibitor of G6PD and NADH oxidase is immunitin; (11) CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB 15050, PF-232798 (Pfizer), and CCR5mAb004; (12) The other drugs for the treatment of HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040). 48. A method for the treatment of an HCV infection, which comprises administering to a patient in need, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. , in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, non-nucleoside inhibitors of HCV , and other drugs for the treatment of HCV, or mixtures thereof. 49. A method for the treatment of an HCV infection, the virus comprises administering to a patient in need, a therapeutically effective amount of a compound of claim 13, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of interferons, ribavirin analogs, NS5b polymerase inhibitors, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, HCV inhibitors that they are not nucleosides, and other drugs for the treatment of HCV, or mixtures thereof. 50. The method of claim 48, wherein: (1) the mentioned interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, IFN -alpha in consensus (nfergen), feron, reaferon, intermax-alpha, r-IFN-beta, infergen + actinmune, IFN-omega with DUROS, albufferon, locteron, Albuferon, Rebif, oral interferon-alpha, IFNalfa-2b XL , AVI-005, PEG-Infergen, and pegylated IFN-beta; (2) ribavirin analogs are selected from the group consisting of rebetol, copegus, viramidine (taribavirin); (3) NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM- 107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (4) NS3 protease inhibitors are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191; (5) alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir), and UT-231B; (6) the hepatoprotectors are selected from the group consisting of IDN-6556, ME 3738, LB-84451, and MitoQ; (7) non-nucleoside HCV inhibitors are selected from the group consisting of benzimidazole derivatives, benzo-1, 2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and (8) the other drugs for the treatment of HCV are selected from the group consisting of zadaxin, nitazoxanide (aligns), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101) , KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacna, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavltuximab , Oglufanida, and VX-497 (merimepodib). 51. A pharmaceutical composition, which comprises a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and a pharmaceutically acceptable carrier or excipient. 52. The pharmaceutical composition of claim 51, which further comprises at least one additional therapeutic agent. 53. A pharmaceutical composition of claim 52, wherein the at least one additional therapeutic agent is metabolized by cytochrome P450 mono-oxygenase. 54. The pharmaceutical composition of claim 52, wherein the at least one additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, non-nucleoside reverse transcriptase inhibitors of HIV, transcriptase inhibitors. Inverse HIV which are nucleosides, HIV transcriptase inhibitors that are nucleotides, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, interferons, ribavirin analogs , NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors, other drugs for the treatment of HCV, and combinations thereof. 55. The pharmaceutical composition of claim 54, wherein: (1) the mentioned HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, Brecanavir, Darunavir, TMC-126, TMC-114, Mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL- 100, DG35, and AG 1859; (2) non-nucleoside HIV reverse transcriptase inhibitors are selected from the group consisting of capravirin, emivirine, delaviridin, efavirenz, nevirapine, (+) calanolide A, etravirin, GW5634, DPC-083, DPC-961 , DPC-963, IV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806; (3) Inhibitors of HIV reverse transcriptase which are nucleotides are selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (± - FTC), D-d4FC, emtricitabine, phosphazide, fozivudine-tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine-tidoxil (formerly HDP 99,0003); and (4) the HIV reverse transcriptase inhibitors that are nucleotides are selected from the group consisting of tenofovir and adefovir; (5) HIV integrase inhibitors are selected from the group consisting of curcumin, curcumin derivatives, quicoric acid, quicoric acid derivatives, 3,5-dicaffeoyl-quinic acid, 3,5-dicarboxylic acid derivatives, quininic, aurintricarboxylic acid, aurintricarboxylic derivatives, phenethyl-ester of caffeic acid, phenethyl ester derivatives of caffeic acid, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, S-1360, zintevir (AR-177), L- 870812, and L-870810, MK-05 8 (raltegravir), B S-538158, GS 364735C, BMS-707035, MK-2048, and BA 011; (6) gp41 inhibitors are selected from the group consisting of enfuvirtide, sifuvirtide, FB006, and TRI-1144; (7) the CXCR4 inhibitor is AMD-070; (8) the input inhibitor is SP01A; (9) The gp120 inhibitor is BMS-488043 or BlockAide / CR; (10) the inhibitor of G6PD and NADH oxidase is immunitin; (11) CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB 15050, PF-232798 (Pfizer), and CCR5mAb004; (12) The other drugs for the treatment of HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV -1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040); (13) The mentioned interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN-alpha (infergen), feron, reaferon, intermax-alpha, r-IFN-beta, infergen + actinmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, oral interferon-alpha, IFNalfa-2b XL, AVI-005, PEG-Infergen, and IFN-beta pegylated; (14) ribavirin analogs are selected from the group consisting of rebetol, copegus, viramidine (taribavirin); (15) NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, 1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107 , R7128 (R4048), VCH-759, PF-868554, and GSK625433; (16) NS3 protease inhibitors are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191; (17) alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir), and UT-231B; (18) the hepatoprotectors are selected from the group consisting of IDN-6556, ME 3738, LB-84451, and MitoQ; (19) non-nucleoside HCV inhibitors are selected from the group consisting of benzimidazole derivatives, benzo-1, 2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and (20) the other drugs for the treatment of HCV are selected from the group consisting of zadaxin, nitazoxanide (aligns), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101) , KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvazin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab , Oglufanida, and VX-497 (merimepodib). 56. A compound of Table 12. 57. A new compound, substantially as described herein. 58. A new pharmaceutical composition or use for the preparation of a medicament, substantially as described herein. 59. A compound of claim 1, as a therapeutic substance. 60. The use of a compound of claim 1, for the manufacture of a medicament for improving the pharmacokinetics of a drug that is metabolized by cytochrome P450 mono-oxygenase, to increase the level in blood plasma of a drug that is metabolized by the mono-oxygenase of cytochrome P450, to inhibit cytochrome P450 mono-oxygenase, for the treatment of an HIV infection, or for the treatment of an HCV infection in a patient. 61. The use of claim 60, wherein the drug that is metabolized by the aforementioned cytochrome P450 mono-oxygenase, is one of HIV protease inhibitor compounds, non-nucleoside reverse transcriptase inhibitors, transcriptase inhibitors. Inverse of HIV are nucleosides, inhibitors of HIV reverse transcriptase that are nucleotides, inhibitors of HIV integrase, inhibitors of gp41, inhibitors of CXCR4, inhibitors of gp120, inhibitors of G6PD and oxidase of NADH, inhibitors of CCR5, other drugs for the treatment of HIV, an interferon, a ribavirin analogue, an NS3 protease inhibitor, an alpha-glucosidase 1 inhibitor, a hepatoprotector, a non-nucleoside inhibitor of HCV, and other drugs for the HCV treatment, or mixtures thereof. 62. The use of claim 61, wherein said medicament is a combination of a compound of claim 1, and one or more therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, transcriptase inhibitors. non-nucleoside HIV reverse transcriptase inhibitors that are nucleosides, HIV transcriptase inhibitors that are nucleotides, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, G6PD inhibitors and oxidase inhibitors of NADH, CCR5 inhibitors, other HIV treatment drugs, ribavirin analogues, NS5b polymerase inhibitors, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, non-nucleoside inhibitors of HCV, and other drugs for the treatment of HCV, and mixtures thereof. 63. The use of claim 62, wherein: (1) the mentioned HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir , darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100 , DG35, and AG 1859; (2) the HIV reverse transcriptase inhibitors that are not nucleosides are selected from the group consisting of capravirin, emivirine, delaviridin, efavirenz, nevirapine, (+) calanolide A, etravirin, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC -120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806; (3) Inhibitors of HIV reverse transcriptase which are nucleotides are selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (± - FTC), D-d4FC, emtricitabine, phosphazide, fozivudine-tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine-tidoxil (formerly HDP 99,0003); and (4) the HIV reverse transcriptase inhibitors that are nucleotides are selected from the group consisting of tenofovir and adefovir; (5) HIV integrase inhibitors are selected from the group consisting of curcumin, curcumin derivatives, chicoric acid, quicoric acid derivatives, 3,5-dicaffeoyl-quinic acid, 3,5-dicarboxylic acid derivatives, quininic, aurintricarboxylic acid, aurintricarboxylic derivatives, phenethyl-ester of caffeic acid, phenethyl ester derivatives of caffeic acid, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, S-1360, zintevir (AR-177), L- 870812, and L-870810, MK-0518 (raltegravir), BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA 011; (6) gp41 inhibitors are selected from group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144; (7) the CXCR4 inhibitor is AMD-070; (8) the input inhibitor is SP01A; (9) the gp120 inhibitor is BMS-488043 or BlockAide / CR; (10) the inhibitor of G6PD and NADH oxidase is immunitin; (11) CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB 15050, PF-232798 (Pfizer), and CCR5mAb004; (12) The other drugs for the treatment of HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV -1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, D-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040); (13) The mentioned interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN-alpha (infergen), feron, reaferon, intermax-alpha, r-IFN-beta, infergen + actinmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, oral interferon-alpha, IFNalfa-2b XL, AVI-O05, PEG-Infergen, and IFN-beta pegylated; (14) ribavirin analogs are selected from the group consisting of rebetol, copegus, viramidine (taribavirin); (15) NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (16) NS3 protease inhibitors are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191; (17) alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir), and UT-231B; (18) the hepatoprotectors are selected from the group consisting of IDN-6556, ME 3738, LB-84451, and MitoQ; (19) non-nucleoside HCV inhibitors are selected from the group consisting of benzimidazole derivatives, benzo-1, 2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and (20) the other drugs for the treatment of HCV are selected from the group consisting of zadaxin, nitazoxanide (aligns), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101) , KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvazin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab , Oglufanida, and VX-497 (merimepodib).
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